Functionalized naphthalene fluorophores

ABSTRACT

Methods for the synthesis and use of functionalized, substituted naphthalenes are described. The functionalized, substituted naphthalenes display useful properties including liquid crystals and fluorescence properties, such as solvatochromatic fluorescence, with high quantum yields, Stoke&#39;s shift, and show emission maxima that are significantly red-shifted.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 61/648,064, filed May 16, 2013, the disclosure of which isincorporated in its entirety by this reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

Portions of the research described herein were supported by U.S.National Science Foundation, Grant CHE0910597. The U.S. Government mayhave certain rights in this technology.

TECHNICAL FIELD

The present disclosure are related to functionalized, substituted,naphthalene fluorophore compounds. The functionalized, substitutednaphthalene fluorophore compounds display novel fluorescent properties.

BACKGROUND

Designing and building small molecules for the purpose of functionenables advancement in fields ranging from pharmaceuticals topesticides. The Diels-Alder (DA) reaction is one of the most powerfuland robust transformations for assembling cyclic molecular frameworks,employing a plethora of diene (4π) and dienophile (2π) componentscapable of delivering a rich diversity of cyclic compounds poised forfunction. One structural variant is the dehydro-Diels-Alder (DDA)reaction, where one, two, or all three of the double bonds of theclassic diene and dienophile are replaced with triple bonds, providingaccess to substituted aromatic compounds not accessible using otherchemistries. The energy price to incorporate the high degree ofprecursor unsaturation required for the formation of aromatic productscan be mitigated by the propensity of cyclohexadiene derivatives toaromatize. Aromatic derivatives, in turn, can be prepared from moresaturated precursors, a process defined as a dehydrogenative DAreaction.

A particularly problematic, but potentially useful dehydrogenative DAreaction involves the use of styrene as the diene component and analkyne dienophile, affording a cycloadduct that can aromatize underoxidative conditions to give naphthalene derivatives (Scheme 1).Problems that can arise when using styrene as the diene range frompolymerizations to [2+2] cycloaddition reactions. One solution is to usevery reactive dienophiles such as maleic anhydride or benzoquinone.However, the desired cycloadducts are typically obtained in low yieldsbecause the reactivity of these dienophiles leads to a second DAreaction with the newly formed diene of the first cycloadduct. Lack ofregioselectivity for the styrenyl DA reaction is also a drawback, whichcan be overcome by carrying out the reaction intramolecularly. Theintramolecular styrenyl DA reaction also suffers from low yields andlong reaction times, producing mixtures of inseparabledihydronaphthalene and naphthalene products.

Continued interest in the development of an efficient styrenyl DAreaction is driven by the need for functionalized naphthalene compoundsthat can serve as valuable building blocks for the synthesis of smallmolecules in many important areas, such as pharmaceuticals, chiralreagents, liquid crystals, and organic dyes. Moreover, theintramolecular styrenyl DA reaction affords a unique functionalizationpattern on the resulting naphthalene derivatives that complements othersynthetic approaches.

Fluorescent-based tools are widely used to monitor environments ofbiological events. Small organic fluorophores are particularly powerfuldue to rapid response times for monitoring real-time events withexcellent spatial resolution. Moreover, their relatively small sizeminimizes disruption of the environment being studied. Thus, new smallmolecule-based chemical sensors are continually being developed. Many ofthese developments involve modifying an existing fluorophore toaccommodate a need. For example, Prodan is a compound whose fluorescentemission and quantum yield is unusually dependent upon solvent polarity;in cyclohexane the fluorescent emission is 410 nm and in water it is 534nm, a bathochromic shift of 124 nm. Prodan is considered to be state ofthe art for application in biological systems and structural variants ofthis probe have been prepared, such as the lipophilic Laurdan; the thiolreactive Acrylodan and Badan; and the amino acid-containing Aladan. Inaddition, a spectrally red-shifted compound, Anthradan, has beenprepared that incorporates an anthracene ring between the electrondonating and electron withdrawing groups; the emission spectra inhexanes is 483 nm, and in methanol 604 nm. The design and synthesis ofnew naphthalene-containing fluorophores could be significantly enhancedby novel methods for the construction of aromatic rings.

SUMMARY

The present disclosure is directed to the design and synthesis of newfunctionalized, substituted, naphthalene compounds which possess uniquestructures and display useful properties, including fluorescentproperties and liquid crystal properties.

According to one embodiment, the present disclosure provides for asubstituted, functionalized naphthalene having a structure

where R¹ is a substituent selected from the group consisting of H,C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, phenyl, aryl, heteroaryl, —S(O)R⁴,—S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ where Y is O, NR⁵, or S; each R² is anelectron donating group selected from —N(R⁶)₂, —OR⁶, and —SR⁶; each R³is H, C₁-C₂₀ alkyl, or combined as ═O; each R⁴, R⁵ and R⁶ isindependently selected from H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, phenyl,aryl, heteroaryl or may come together to form a cyclic structure; X isCH₂, C(R⁶)₂, C(CO₂Alkyl)₂, O, NTs, NH, NCOR⁵ or NR⁵; n is an integerfrom 0 to 2; m is an integer from 1 to 4, provided that either R¹ is oneof —S(O)R⁴, —S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ or R³ is ═O.

According to another embodiment, this disclosure provides forfunctionalized substituted naphthalenes as described herein wherein thenaphthalene is a fluorophore.

According to another embodiment, the present disclosure provides forfunctionalized substituted naphthalenes as described herein wherein thenaphthalene is a solvatochromatic fluorophore.

According to another embodiment, this disclosure provides forfunctionalized substituted naphthalenes as described herein wherein thenaphthalene is a liquid crystal.

Still further embodiments of the present disclosure provide for a methodof synthesizing a substituted, functionalized naphthalene as describedherein, the method comprising reacting a 2′-alkynyl substitutedhalostyrene by a dehydrogenative intramolecular dehydro Diels Alderreaction in the presence of microwave irradiation to form a halosubstituted naphthalene; and reacting the halo substituted naphthaleneto a cross coupling reaction to form a functionalized naphthalene havinga structure

where R¹ is a substituent selected from the group consisting of H,C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, phenyl, aryl, heteroaryl, —S(O)R⁴,—S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ where Y is O, NR⁵, or S; each R² is anelectron donating group selected from —N(R⁶)₂, —OR⁶, and —SR⁶; each R³is H, C₁-C₂₀ alkyl, or combined as ═O; each R⁴, R⁵ and R⁶ isindependently selected from H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, phenyl,aryl, heteroaryl or may come together to form a cyclic structure; X isCH₂, C(R⁶)₂, C(CO₂Alkyl)₂, O, NTs, NH, NCOR⁵ or NR⁵; n is an integerfrom 0 to 2; m is an integer from 1 to 4, provided that either R¹ is oneof —S(O)R⁴, —S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ or R³ is ═O.

Other embodiments of the present disclosure provide a method forfluorescing a fluorescent functionalized naphthalene having a structure

where R¹ is a substituent selected from the group consisting of H,C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, phenyl, aryl, heteroaryl, —S(O)R⁴,—S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ where Y is O, NR⁵, or S; each R² is anelectron donating group selected from —N(R⁶)₂, —OR⁶, and —SR⁶; each R³is H, C₁-C₂₀ alkyl, or combined as ═O; each R⁴, R⁵ and R⁶ isindependently selected from H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, phenyl,aryl, heteroaryl or may come together to form a cyclic structure; X isCH₂, C(R⁶)₂, C(CO₂Alkyl)₂, O, NTs, NH, NCOR⁵ or NR⁵; n is an integerfrom 0 to 2; m is an integer from 1 to 4, provided that either R¹ is oneof —S(O)R⁴, —S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ or R³ is ═O. The methodcomprises irradiating the functionalized naphthalene withelectromagnetic radiation and measuring the amount of fluorescent lightemitted by the irradiated functionalized naphthalene.

Still other embodiments of this disclosure provides for a fluorescentsensor comprising a functionalized, substituted naphthalene having astructure as described herein.

Still other embodiments of the present disclosure provides for a liquidcrystal display, photo voltaic device, or conjugated polymer comprisinga functionalized, substituted naphthalene having a structure asdescribed herein.

Still other embodiments of the present disclosure proves for asolvatochromatic fluorophore comprising a functionalized, substitutednaphthalene having a structure as described herein.

Still further embodiments provide a functionalized naphthalenefluorophore having a structure: a)1-(5-(dimethylamino)-2′,2′-dimethyl-1,3-dihydrospiro[cyclopenta[b]naphthalene-2,5′-[1,3]dioxan]-9-yl)ethanone;b)1-(5-(dimethylamino)-2′,2′-dimethyl-1,3-dihydrospiro[cyclopenta[b]naphthalene-2,5′-[1,3]dioxan]-9-yl)-2,2-dimethylpropan-1-one;c)1-(2,2-bis(((tert-butyldimethylsilyl)oxy)methyl)-8-(dimethylamino)-2,3-dihydro-1H-cyclo-penta[b]naphthalen-4-yl)ethanone;d)1-(2′,2′-dimethyl-5-(pyrrolidin-1-yl)-1,3-dihydrospiro[cyclopenta[b]naphthalene-2,5′-[1,3]dioxan]-9-yl)ethanone;e)1-(8-(dimethylamino)-2,2-bis(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone;f)1-(8-(dimethylamino)-2,2-bis(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)-2,2-dimethylpropan-1-one;g)1-(2,2-bis(hydroxymethyl)-8-(pyrrolidin-1-yl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone;h)(8-(dimethylamino)-4-pivaloyl-2,3-dihydro-1H-cyclopenta[b]naphthalene-2,2-diyl)bis(methylene)bis(undec-10-enoate);i)6-((tert-butyldimethylsilyl)oxy)-1-(8-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)hexan-1-one;j)1-(8-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)-6-hydroxyhexan-1-one;k)9-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)-7-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one; 1)7-(dimethylamino)-9-(4-(2-hydroxyethoxy)phenyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;m)9-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-7-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;n)7-(dimethylamino)-9-(4-(hydroxymethyl)phenyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;o)2-(4-(6-dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)dione; p)1-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzyl)-1H-pyrrole-2,5-dione;q) ethyl2-((tert-butoxycarbonyl)amino)-3-(1-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzyl)-2,5-dioxopyrrolidin-3-yl)thio)propanoate;r)4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzaldehyde;s)7-(dimethylamino)-9-(4-ethynylphenyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;t) methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)propanoate;u)4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzylundec-10-enoate; v)5-(Dimethylamino)-9-phenyl-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;w)6-(Dimethylamino)-9-phenyl-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;x)5-(Dimethylamino)-9-(trimethylsilyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;y)6-(Dimethylamino)-9-(trimethylsilyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;z) 5-(Dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one; aa)6-(Dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one; or bb)8-(Dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one.

Further embodiments provide a peptide or protein comprising a modifiedamino acid residue comprising a substituted naphthalene fluorophore.

Still further embodiments of the present disclosure provide afunctionalized naphthalene fluorophore having a structure:

where R¹ is a substituent selected from the group consisting of H,C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, an NMR active isotope or an alkyl or alkoxygroup comprising an NMR active isotope, a substituted silyl,trialkylsilyl, diphenylalkylsilyl, triphenylalkylsilyl, a substitutedphosphorous, dialkylphosphino, diphenylphosphino, phenyl, aryl,heteroaryl, —S(O)R⁴, —S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ where Y is O,NR⁵, or S; each R² is a halogen, an NMR active isotope or an alkyl oralkoxy group comprising an NMR active isotope, a substituted silyl,trialkylsilyl, diphenylalkylsilyl, triphenylalkylsilyl, a substitutedphosphorous, dialkylphosphino, diphenylphosphino, or an electrondonating group selected from —N(R⁶)₂, —OR⁶, and —SR⁶; each R³ is H,C₁-C₂₀ alkyl, an NMR active isotope or an alkyl or alkoxy groupcomprising an NMR active isotope, a substituted silyl, trialkylsilyl,diphenylalkylsilyl, triphenylalkylsilyl, a substituted phosphorous,dialkylphosphino, diphenylphosphino, or combined as ═O; each R⁴, R⁵ andR⁶ is independently selected from H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, asubstituted silyl, trialkylsilyl, diphenylalkylsilyl,triphenylalkylsilyl, a substituted phosphorous, dialkylphosphino,diphenylphosphino, an NMR active isotope or an alkyl or alkoxy groupcomprising an NMR active isotope, substituted or unsubstituted phenyl,aryl, heteroaryl, benzyl, or may come together to form a cyclicstructure; X is CH₂, C(R⁶)₂, C(CO₂Alkyl)₂, O, NTs, NH, NCOR⁵ or NR⁵; nis an integer from 0 to 2; m is an integer from 1 to 4, provided thateither R¹ is one of —S(O)R⁴, —S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ or the R³groups are combined as ═O.

Other embodiments of the present disclosure provide methods formonitoring a tagged compound in vivo comprising tagging a biologicalcompound with a functionalized naphthalene fluorophore according toclaim 4; and monitoring the tagged compound using a spectroscopictechnique.

Other embodiments of the compositions and methods of the presentdisclosure will be apparent to one of skill in the art based uponknowledge acquired by reading this disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

The various embodiments of the present disclosure will be betterunderstood when read in conjunction with the following Drawings wherein:

FIG. 1 is an X-ray crystal structure ofN′-(1-(2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)hexa-4,5-dien-1-ylidene)-4-methylbenzene-sulfonohydrazide(3).

FIG. 2A is the absorption (dashed line) and fluorescent emission (solidlines) spectra of1-(6-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanonein organic solvents of different polarity. Absorption spectrum wasrecorded in CH₂Cl₂. The excitation wavelength was 334 nm.

FIG. 2B is the absorption (dashed line) and fluorescent emission (solidlines) spectra of1-(7-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanonein organic solvents of different polarity. Absorption spectrum wasrecorded in CH₂Cl₂. The excitation wavelength was 334 nm.

FIG. 2C is the absorption (dashed line) and fluorescent emission (solidlines) spectra of1-(8-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanonein organic solvents of different polarity. Absorption spectrum wasrecorded in CH₂Cl₂. The excitation wavelength was 334 nm.

FIGS. 3A-3I show the emission spectra for1-(6-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanonein different solvents, QY is fluorescence quantum yield vs PRODAN inDMSO (91%); excitation wavelength was 334 nm.

FIGS. 4A-4I show the emission spectra for1-(7-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanonein different solvents, QY is fluorescence quantum yield vs PRODAN inDMSO (91%); excitation wavelength was 334 nm.

FIGS. 5A-5I show the emission spectra for1-(8-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanonein different solvents, QY is fluorescence quantum yield vs PRODAN inDMSO (91%); excitation wavelength was 334 nm.

FIG. 6 shows the emission spectra for1-(6-(pyrrolidin-1-yl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone,QY is fluorescence quantum yield vs PRODAN in DMSO (91%); excitationwavelength was 334 nm.

FIG. 7 shows the emission spectra for1-(6-(piperidin-1-yl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone,QY is fluorescence quantum yield vs PRODAN in DMSO (91%); excitationwavelength was 334 nm.

FIG. 8 shows the emission spectra for1-(6-morpholino-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone, QYis fluorescence quantum yield vs PRODAN in DMSO (91%); excitationwavelength was 334 nm.

FIG. 9 shows the emission spectra for1-(6-(benzylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone,QY is fluorescence quantum yield vs PRODAN in DMSO (91%); excitationwavelength was 334 nm.

FIG. 10 shows the emission spectra for1-(6-(phenylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone,QY is fluorescence quantum yield vs PRODAN in DMSO (91%); excitationwavelength was 334 nm.

FIG. 11 shows the emission spectra for1-(6-((4-methoxyphenyl)amino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone, QY is fluorescence quantum yield vs PRODAN in DMSO (91%);excitation wavelength was 334 nm.

DETAILED DESCRIPTION

The present disclosure describes substituted, functionalizednaphthalenes which display useful properties and uses as fluorophores,solvatochromatic fluorophores, components of photo voltaic devices,structural components in conjugated polymers, pharmaceuticals, lightharvesting components, and liquid crystals. The present disclosureutilizes an intramolecular didehydro-Diels-Alder (DDA) reaction betweena styrene and an alkyne linked by a tether for the synthesis of newsubstituted naphthalene compounds that can be used as fluorescent tags.It was envisioned that a number of modifications can be made, eitherlinearly or combinatorially, to the DDA precursors and/or to the DDAproducts, leading to novel substituted naphthalene compounds that willbe tested for their general chemical and fluorescent properties such as:molecular absorbance, quantum yield, excitation wavelength, emissionwavelength, Stokes shift, fluorescent lifetime, photostability, andsolubility, that are essential for sensing applications. Examples ofmodifications to the precursor include but are not limited to,substitution at the terminus of the alkyne (R¹), the aromatic ring (R²),the double bond (R³) and/or the tether (XYZ). Examples of modificationsthat can be made to the product include but are not limited to any orall of the following: conversion of R¹ to R⁴, R² to R⁵, R³ to R⁶, and/orXYZ to ABC.

As generally used herein, the terms “include” and “have” mean“comprising”. As generally used herein, the term “about” refers to anacceptable degree of error for the quantity measured, given the natureor precision of the measurements. Typical exemplary degrees of error maybe within 20%, 10%, or 5% of a given value or range of values.Alternatively, and particularly in biological systems, the term “about”may mean values that are within an order of magnitude, potentiallywithin 5-fold or 2-fold of a given value.

Recently, in our studies directed towards expanding the scope of thethermal [2+2] cycloaddition reaction of allene-ynes, naphthalene 2 wasobtained and none of the anticipated [2+2] cycloaddition product betweenthe allene and the alkyne of 1 upon microwave irradiation inortho-dichlorobenzene at 225° C. for 5 min. While the ¹H NMR and ¹³C NMRspectra of 2 contained well-defined resonances in the aromatic regiondiagnostic of a cyclopentanaphthalene, verification of the productstructure having a linear or angular arrangement was elusive. Thecyclopentanaphthalene derivative possessing a linear arrangement of thethree rings could originate from the uncommon IMDA discussed above. Theangular cyclopentanaphthalene could arise from a thermal [2+2]cycloaddition reaction between the double bond of the styrenyl group andthe alkynone, followed by a 4π-electrocyclic ring opening of thecorresponding cyclobutene to yield a new diene. Isomerization of theappended double bond from the Z- to the E-isomer, followed by a6π-electrocyclic ring closing and aromatization would yield the angularproduct. The linear structure of compound 2 was confirmed by an X-raycrystal structure of o-nitrophenyl sulfonyl hydrazone 3. The outstandingselectivity of this IMDA reaction for the naphthalene product over thedihydronaphthalene product (1:0), the high yield, and an overallinterest in naphthalene derivatives compelled us to study this reactionfurther.

Or investigations differ from existing methods for the synthesis ofnaphthalene derivatives via the IMDA reaction of styrenes, all of themsharing a few common features such as 1) the enyne precursors containeither a heteroatom and/or a carbonyl group(s) within the tether (mainlyamides and esters); 2) limited functionality on the terminus of thealkyne, usually trimethylsilyl (TMS) or phenyl groups, or a hydrogenatom; 3) reaction conditions requiring high temperatures and longreaction times; and 4) most naphthalene products are contaminated withvarying quantities of dihydronaphthalene byproducts. Moreover, ourinitial result directly opposes the work reported by Matsubara, whosuggests that a TMS group on the terminus of the alkyne is necessary forthe exclusive formation of the naphthalene over the dihydronaphthaleneproduct.

A concise synthesis of a dehydrogenative IMDA styrenyl precursor 5 wasaccomplished in 3 steps, and in a manner entirely analogous to that usedfor the preparation of 1. Aldehyde 4 is prepared by a PCC oxidation ofcommercially available 5-hexyn-1-ol in 81% yield. Next, reaction of thelithium or sodium salt of diethyl benzylphosphonate with aldehyde 4affords the styrene moiety of 5 in 68% yield. Deprotonation of thealkyne terminus with n-BuLi followed by acetylation of the acetylideproduces 5 in 69% yield. For the ensuing IMDA reaction, solvents withlower boiling points were considered because of difficulties in removinghigh boiling o-dichlorobenzene.

Microwave irradiation of styrene 5 in either 1,2-dichloroethane (DCE) at180° C. for 30 min or 1,1,1-trifluorotoluene at 180° C. for 180 minutesafforded the cyclopenta-naphthalene derivative 6 in nearly quantitativeyield with no additional purification required of the final product(entries 1 and 2, Table 1). With conditions for an efficient and highyielding IMDA reaction utilizing a lower boiling solvent in hand, scopeand limitations investigations were initiated. First, substitution onthe aryl group was examined; exchanging a hydrogen atom for a chlorineatom was deemed valuable, enabling access to a wide-range of naphthalenederivatives via palladium-catalyzed cross coupling reactions. Moreover,a chlorine atom is more stable and accessible than other halides orgroups used for coupling, such as triflates. Styrenyl derivatives 5b,5c, and 5d were prepared and subjected to microwave irradiation. Thepara-chlorostyrene 5b gave 7-chloronaphthalene 6b in quantitative yieldafter 200 min (entry 3). The ortho-chlorostyrene 5c also produced onlyone product, the 5-chloronaphthalene 6c in 86% yield, even though twoproducts are possible (entry 4). The meta-chlorostyrene 5d gave aninseparable 1.4:1 mixture of the 6-chloro- and 8-chloronaphthalenes, 6dand 6d′ in 79% yield (entry 5).

Next, a number of functional groups on the terminus of the alkyne wereinvestigated in the IMDA reaction. Substitution of the alkyne with aphenyl methanone gave the cycloadduct 6e in quantitative yield after 90min (entry 6). Reaction scale did not affect the yield of this reaction,but it did have an affect on the reaction time; for example, 50 mg of 5eafforded 6e in 90 min, while 200 mg of 5e required a reaction time of130 min. Placement of the methylsulfonyl and phenylsulfonyl groups onthe terminus of the alkyne to produce 5f and 5g resulted in a facileIMDA reaction to give 6f and 6g in 78% and 89% yield, respectively(entries 7 and 8). Sulfoxide 5h gave a slightly lower yield, but stillafforded the naphthalene product 6h selectively (entry 9). Similarly,the diethyl phosphonate substituted alkyne 5i produced 6i in greaterthan 95% yield in 150 min (entry 10). Alkynal 5j affords the naphthalene6j in 83% yield in 45 min (entry 11). A substrate with a methyl ester onthe alkyne terminus 5k, slowed the reaction considerably, requiring 600min to obtain complete conversion to 6k in 76% yield (entry 12). Thereaction time could be shortened from 600 to

TABLE 1 Microwave-Assisted Dehydrogenative Diels-Alder Reaction

entry 5 R¹ R² X time 6 yield (%) 7 yield (%)  1 5a C(O)CH₃ H —CH₂—30 >95 (6a) 0 (7a)  2^(a) 5a C(O)CH₃ H —CH₂— 180 >95 (6a) 0 (7a)  3 5bC(O)CH₃ p-Cl —CH₂— 200 >95 (6b, 7-chloro) 0 (7b)  4^(b) 5c C(O)CH₃ o-Cl—CH₂— 180 86 (6c, 5-chloro) 0 (7c)  5^(b) 5d C(O)CH₃ m-Cl —CH₂— 180 79(6d, 6d′ 6-, 8- 0 (7d)  6 5e C(O)Ph H —CH₂— 90 >95 (6e) 0 (7e)  7^(c) 5fSO₂CH₃ H —CH₂— 20 76 (6f) 0 (7f)  8 5g SO₂Ph p-Cl —CH₂— 15 89 (6g,7-chloro) 0 (7g)  9 5h SOPh p-Cl —CH₂— 60 75 (6h, 7-chloro) 0 (7h)10^(c) 5i P(O)OEt₂ p-Cl —CH₂— 150 >95 (6i, 7-chloro) 0 (7i) 11 5j CHOp-Cl —CH₂— 45 83 (6j, 7-chloro) 0 (7j) 12 5k CO₂CH₃ H —CH₂— 600 76 (6k)0 (7k) 13^(d) 5k CO₂CH₃ H —CH₂— 90 >95 (6k) 0 (7k) 14^(a,b) 5l C(O)CH₃ H—(CH₂)₂— 50 >95 (6l) 0 (7l) 15^(c) 5m C(O)CH₃ o-Cl —C(CO₂Et)₂— 30 >95(6m, 5-chloro) 0 (7m) 16 5n C(O)CH₃ H —O— 30 28 (6n) 15 (7n) 17 5oC(O)CH₃ H —NTs— 10 30 (6o) 56 (7o) 18^(b) 5p C(O)CH₃ o-Cl —NTs— 10 24(6p, 5-chloro) 48 (7p) 19^(b) 5p C(O)CH₃ o-Cl —NTs— 10 59 (6p, 5-chloro)6 (7p) ^(a)Reaction performed using 1,1,1-trifluorotoluene as solvent;^(b)Reaction performed using o-dichlorobenzene (DCB) as solvent;^(c)Reaction performed in DCB at 225° C.; ^(d)Reaction performed at 300°C. in DCB.90 min by heating to 225° C. in o-dichlorobenzene; this also resulted inan improved yield of 97% (entry 13). The rate of these IMDA reactions(entries 1-13) corresponds well with Frontier Molecular Orbital Theoryand HOMO-LUMO gaps.

Finally, structural changes in the tether were examined. Extending thetether by one methylene unit gave precursor 5l that required heating at300° C. for 50 min in o-dichlorobenzene but provided the product 6l inquantitative yield (heating at 225° C. for 240 minutes resulted inrecovery of starting material). To the best of our knowledge, this isthe first successful styrenyl IMDA reaction using a four-atom tether toprovide naphthalene containing an additional six-membered ring. Reactionof the precursor 5m with an all carbon tether possessing a diestermoiety afforded only 6m in greater than 95% yield in 30 min (entry 15).Next, an ether tether was used to connect the styrene and the alkyne.The cycloaddition of 5n was complete in 30 min and gave a 2:1 ratio ofthe naphthalene 6n to the dihydronaphthalene 7m (entry 16). Thetoluenesulfonamide substrate 5o also afforded a mixture of products, butin a 2:1 ratio of the dihydronaphthalene 7o to naphthalene 6o in 10 minin a combined yield of 86% (entry 17). The case of thetoluenesulfonamide tether with a chloro group on the aromatic ring alsoprovided a 2:1 ratio of the dihydronaphthalene 7p to naphthalene 6p in10 min in a combined yield of 72% (entry 18). If 5p was heated to 225°C. for 10 min, nearly a 10:1 ratio of naphthalene 7p todihydronaphthalene 6p was obtained in 65% yield (entry 19). For each ofthe heteroatom-containing tethers a mixture of products was observed;furthermore, when the reaction time was extended to 120 min for entry5p, the ratio of naphthalene 6p to internal standard did not change, butthe dihydronaphthalene 7p was no longer evident by ¹H NMR, suggestingthat dihydronaphthalene 7p is not converted to 6p. Separation ofdihydronaphthalene 7p and naphthalene 6p could not be accomplished bycolumn chromatrography, so attempts were made to oxidize the mixture to6p using cerric ammonium nitrate (CAN), dichlorodicyanobenzoquinone(DDQ), Pd/C, or O₂. All reactions gave either complete decomposition ofthe naphthalene and dihydronaphthalene products, or selectivedecomposition of the dihydronaphthalene.

These naphthalene derivatives may be used as potential candidates forapplication to the ever-increasing field of small molecule fluorescentprobes. Consequently, reaction of 6b to a palladium-catalyzed aminationreaction using RuPhos precatalyst, LHMDS and N,N-dimethylamine affordedcyclopentanaphthalene 8 in 70% yield. Compound 8 was stronglyfluorescent with an absorption maxima of 377 nm and an emission maximaof 510 nm. The emission maximum was significantly red-shifted from thestructurally similar Prodan, which has an emission maxima of 440 nm indichloroethane. Moreover, a quantum yield of 99% was measured forcompound 8 in dichloroethane.

A thermal dehydrogenative Diels-Alder reaction affordscyclopenta-naphthalenes in excellent yield. For all cases examined, thestyrene functioned only as a diene contrary to literature reports ofcompeting reactivity. For the heteroatom-containing tether,dihydro-naphthalenes were obtained along with the naphthalene products.Investigations are underway to understand the mechanism by which thesetwo products are formed. Finally, it has been demonstrated the syntheticutility of this method by preparing fluorophore 8 with interestingphotophysical properties.

Prodan 8a is a compound whose fluorescent emission and quantum yield isunusually dependent upon solvent polarity; in cyclohexane thefluorescent emission is 410 nm and in water it is 534 nm, a bathochromicshift of 124 nm. Prodan is considered to be state of the art forapplication in biological systems and structural variants of this probehave been prepared, such as the lipophilic Laurdan 8b; the thiolreactive Acrylodan 8c and Badan 8d; and the amino acid-containing Aladan8e. In addition, a spectrally red-shifted compound, Anthradan 8f, hasbeen prepared that incorporates an anthracene ring between the electrondonating and electron withdrawing groups; the emission spectra inhexanes is 483 nm, and in methanol 604 nm.

Prodan Derviatives

For each of these Prodan derivatives, the donor-acceptor substituentsare located along the x-axis (longer axis) of the naphthalene pi-system,and the amino group can be characterized as exonuclear and stericallyunhindered. For the anthracene analog, even though the emissionwavelength was significantly red-shifted, the quantum efficiency waslower. The design and synthesis of new naphthalene-containingfluorophores could be significantly enhanced by novel methods for theconstruction of aromatic rings. As described herein, the synthesis andfluorescent properties of a series of novel Prodan derivatives, enabledby the microwave-assisted dehydrogenative Diels-Alder reaction, wherebythe acceptor and/or donor substituents are located along the y-axis(shorter axis) of the conjugated system, providing a more rigidconjugated structure between the acceptor and donor groups.

With an eye towards the preparation of a series of aminonaphthalenederivatives, cross coupling reactions were examined for the introductionof electron donating amine groups via the chloronaphthalene. For thisprocess, the versatile palladium-catalyzed amination of aryl halides hasemerged as a valuable tool. For the first generation derivative,dimethylamine and chloronaphthalenes 6b, 6c, 6d and 6d′ were selected sothat photophysical properties of this first generation of derivativescould be directly compared to that of Prodan (Scheme 4). The couplingreaction of 6b and 6d using a commercially available RuPhos precatalyst(2.5 mol %) and LHMDS in dry THF afforded the correspondingN,N-dimethylamine substituted cyclopentanaphthalenes 10 and 12 in 70%and 49% yield, respectively. Different palladium sources (Pd(OAc)₂) andbases (K₃PO₄, CsCO₃) were also screened, but all resulted in loweryields of the coupling products. Interestingly, the inseparable mixtureof 6d and 6d′ gave two products: 11 in 52% yield along with 6a. It ishypothesized that 6a arises from a palladium catalyzed-dehalogenationreaction of 6d′ facilitated by the close proximity of the methyl ketone.Next, a number of amines were coupled with 6b. Secondary cyclic aminessuch as pyrrole, piperidine, and morpholine gave the correspondingtertiary amines 13, 14, and 15 in 59%, 45% and 58% yield, respectively.Primary amines such as benzylamine, aniline, and para-methoxyanilinewere also successfully coupled with 6b to afford 16, 17 and 18 in 89%,78% and 71% yield, respectively.

With a series of compounds with the donor and acceptor groups separatedby a naphthalene nucleus in hand, fluorescent absorption and emissionmaximum were measured in methylene chloride, along with quantum yields.Notable trend's for this series of solvatochromic compounds wereobserved. Compound 12 containing a 1,5-substituted cyclopentanaphthalenemoiety absorbed light at a much shorter wavelength (332 nm) andfluoresced at a much longer wavelength (562 nm) than either the 1,7- or1,6-disubstituted compounds 10 or 11 (absorption and emission maximum˜375 nm and 510 nm). The tertiary cyclic amine series showed a range ofabsorption maxima (355-390 nm) while the emission maxima remainedconstant (508-515 nm). The emission spectra of the secondary amines 16,17, and 18 were significantly blue-shifted (482-492 nm) when compared tothe tertiary amines, but there were not significant differences inabsorption or emission maxima between each of the secondary amines.Finally, the quantum yields for all fluorophores in Scheme 4 wereextremely high, with one exception, compound 12.

Finally, solvatochromic properties for compounds 10, 11, and 12 weremeasured in a number of solvents varying in polarity (FIG. 2). Severalimportant findings emerged from these measurements, the first being thatin the case of all fluorophores, as the solvent polarity increases theemission maxima are significantly red-shifted. For example, the emissionmaxima for compounds 10, 11, and 12 are 466, 445 and 480 nm incyclohexane and 578, 605, and 634 nm in ethanol, respectively. Moreover,the emission spectra are significantly red-shifted from that of Prodan,which emits at 389 nm in hexanes and 485 nm in ethanol. Red-shiftedfluorescent emissions are important for biological applications wherebackground fluorescence can limit the magnitude of the fluorescentchange.

TABLE 2 Spectroscopic properties of dyes 10, 11 and 12 in comparison toProdan  

 

   

En- λ_(abs) ^(a) λ_(em) ^(b) QY λ_(abs) ^(a) λ_(em) ^(b) QY^(c) λ_(abs)^(a) λ_(em) ^(b) QY^(c) λ_(abs) ^(a) λ_(em) ^(b) QY^(c) try Solvent nmnm % nm nm % nm nm % nm nm %  1 n-Hexane 340 389 2.0 / / / / / / / / / 2 Cyclohexane / / / 314 480 28 363 445 8 373 466 45  3 Toluene 346 41656 322 520 47 368 481 25 376 490 62  4 1,4-Dioxane 346 422 75 319 534 44376 495 46  5 THF 348 430 78 330 543 39 370 505 34 377 497 75  6 CH₂Cl₂355 440 98 334 562 60 372 509 82 377 510 99  7 CHCl₃ / / / 334 562 40373 514 41 377 516 77  8 Acetonitrile 350 455 80 316 590 23 370 545 18375 529 99  9 DMSO 357 462 91 334 598 48 374 558 37 377 536 85 10 EtOH362 485 71 334 634 / 374 605 3 377 578 5 ^(a)Maximum absorption.^(b)Maximum emission. ^(c)Fluorescence quantum yield vs Prodan in DMSO(91%), excitation was 334 nm (10⁻⁵M solutions).

According to specific embodiments, the substituted, functionalizednaphthalenes synthesized by the methods of the present disclosure mayhave a molecular structure according to Formula I.

According to Formula I, R¹ may be a substituent selected from the groupconsisting of H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, phenyl, aryl, heteroaryl,—S(O)R⁴, —S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ where Y is O, NR⁵, or S; eachR² may be a halogen or an electron donating group selected from —N(R⁶)₂,—OR⁶, and —SR⁶; each R³ may be H, C₁-C₂₀ alkyl, or combined as ═O; eachR⁴, R⁵ and R⁶ may be independently selected from H, C₁-C₂₀ alkyl, C₁-C₂₀alkoxy, phenyl, aryl, heteroaryl or may come together to form a cyclicstructure; X is CH₂, C(R⁶)₂, C(CO₂Alkyl)₂, O, NTs, NH, NCOR⁵ or NR⁵; nis an integer from 0 to 2; m is an integer from 1 to 4. According tocertain embodiments, suitable fluorescence may be observed when one ofR¹ or R³ has a pi bond that is in conjugation with the pi system of thenaphthalene ring. Therefore, according to the naphthalenes of thepresent disclosure, at least one of R¹ and R³ will comprise a pi bond inconjugation with the pi system of the naphthalene ring, i.e., providedthat either R¹ is one of —S(O)R⁴, —S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴and/or R³ is ═O. The R² group in the various embodiments may further beselected from C₁, C₁-C₂₀ alkyl groups or phenyl, aryl, or heteroarylgroups when more than one R² group is present provided that at least oneR² group is an electron donating group. Other electron donating groupsthat may be suited as R² such as groups with an atom having a lone pairof electrons that is attached either directly to the carbon of thenaphthalene ring or attached indirectly to a carbon of the naphthalenering by a pi system that is in conjugation with the pi system of thenaphthalene. Examples include heteroaromatic groups, phenyl or aromaticgroups with a conjugated electron donating group.

The structure according to Formula I, may further comprise substitutionon the carbons of the naphthalene ring, or on the carbons of thenon-aromatic ring, such as the cyclopentyl ring (where n=1). Forexample, according to certain embodiments, the naphthalene ring may besubstituted on two adjacent carbons with at least one carbocyclic orheterocyclic ring fused to the naphthalene ring. In specificembodiments, the fused ring may be at least one aromatic ring or aheteroaromatic ring. For example, according to certain embodiments thenaphthalene ring may have a phenyl ring(s) fused to the naphthalenering, thereby making an anthracenyl-type ring system, aphenanthracenyl-type ring system. The ring(s) fused to the naphthalenerings may be substituted with various substituents, such as the onesdescribed herein, and including electron withdrawing or electrondonating groups (such as R²-type groups). Without intending to belimited by any interpretation, it is believed that changing thesubstitution and/extending the pi system of the naphthalene system maybe used to tune the optical properties of the compound, such as thefluorescent properties.

In specific embodiments, R¹ may be —S(O)R⁴, —S(O)₂R⁴, P(O)(OR⁴)₂, or—C(Y)R⁴, Y may be O or NR⁵ and R⁴ and R⁵ may independently be H, C₁-C₂₀alkyl, C₁-C₂₀ alkoxy, phenyl, or aryl, and each R² is Cl, —N(R⁶)₂, or—OR⁶, where each R⁶ may be H, C₁-C₂₀ alkyl, substituted or unsubstitutedphenyl, or come together to form a cyclyl or heterocyclyl structurehaving 4-5 carbon atoms. According to particular embodiments, R¹ may—C(Y)R⁴, Y is O, and R⁴ may be H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, phenyl,or aryl.

In still other embodiments of the functionalized naphthalenes describedherein, wherein R² may be Cl, such as in the product of thedehydrogenative dihydro Diels Alder reaction, or alternatively, in theresulting fluorescent compound. In other embodiments, at least one R²may be an electron donating group, such as, —N(R⁶)₂, or —OR⁶, where eachR⁶ may be H, C₁-C₂₀ alkyl, substituted or unsubstituted phenyl, or cometogether to form a cyclyl or heterocyclyl structure having 4-5 carbonatoms. According to these embodiments, specific fluorescent properties,such as solvatochromic properties, may be observed with thesesubstituted functionalized naphthalenes.

According to other embodiments, the R³ groups may together form acarbonyl group (C═O). According to these embodiments, the R¹ group neednot be in conjugation with the naphthalene ring in order to observefluorescence. In specific embodiments, where the R³ groups are combinedas a carbonyl (C═O), the X group may be CH₂ (i.e., a cyclic ketone),C(R⁶)₂ (i.e., a cyclic ketone), O (a lactone), or NTs (an amide), R¹ maybe any of the groups described herein and in specific embodiments may beH, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, phenyl, aryl, or heteroaryl, and each R²may be Cl, or an electron donating group such as —N(R⁶)₂, or —OR⁶, whereeach R⁶ is H, C₁-C₂₀ alkyl, substituted or unsubstituted phenyl, or cometogether to form a cyclyl or heterocyclyl structure having 4-5 carbonatoms. As used herein the term “cyclyl” means a cyclic group where thetwo R⁶ groups on the nitrogen come together to from a four, five, six orseven membered ring including 3-6 substituted or unsubstituted carbonatoms and the nitrogen of the electron donating group. As used hereinthe term “heterocyclyl” means a heterocyclic group where the two R⁶groups on the nitrogen come together to from a four, five, six or sevenmembered ring including 2-5 substituted or unsubstituted carbon atoms,at least one second heteroatom such as an O, N, P, or S, and thenitrogen of the electron donating group.

According to specific embodiments, the substituted functionalizednaphthalenes of the present disclosure may have a structure:

As described in detail herein, the substituted functionalizednaphthalenes of the present disclosure, such as the naphthalenesaccording to Formula I, may be a fluorophore. That is, the substitutedfunctionalized naphthalenes may absorb electromagnetic radiation at ashort wavelength, such as a wavelength in the visible or UV region ofthe electromagnetic spectrum and emit or fluoresce light having a longerwavelength than the absorption wavelength. In particular embodiments,the fluorescent naphthalenes described herein may display a fluorescentemission maximum at a wavelength of from 450 nm to 650 nm. Emissions inthese wavelengths may be of particular interest since many conventionalfluorophores do not emit near the red end of the spectrum. The red shiftobserved for the present fluorophores make them potentially useful in anumber of applications such as an imaging fluorescent agent, a taggingfluorescent agent, an ultimately use in medical diagnostics.

In specific embodiments, the various substituted functionalizednaphthalenes of the present disclosure may be solvatochromicfluorophores. Solvatochromic fluorophores display different fluorescentproperties, such as emission maxima, absorption maxima, quantum yields,depending on the solvents that they are dissolved or suspended in.Solvatochromism may allow the fluorescent species, such as a taggedcompound, metabolite, cellular component, environmental contaminantetc., to be traced as it migrates from one solvated environment toanother, for example by monitoring the fluorescent emission maximum ofthe fluorescent species. Conventional solvatochromic fluorophores, suchas Prodan, may be limited because of their short wavelength emissionmaximum which can overlap with emission wavelength of other systemcomponents. In contrast, the solvatochromic fluorescent naphthalenes ofthe present disclosure may display a fluorescent emission maximum aswavelengths at least 50 nm longer than the fluorescent emission maximumof Prodan in the same solvent, and in certain embodiments up to 200 nmlonger than the emission maximum of Prodan in the same solvent. Thus,the solvatochromic naphthalenes may display desired fluorescentproperties not present in conventional sovlatochromic fluorophores.

Due to the relatively planar and rigid structure of the functionalizednaphthalenes of the present disclosure, combined with their lightabsorption and emission properties, in certain embodiments thefunctionalized naphthalenes may be used as a liquid crystal.

Still further embodiments of the present disclosure provide methods forsynthesizing the fluorescent functionalized naphthalenes describedherein. According to the various embodiments, the methods comprisereacting a 2′-alkynyl substituted halostyrene by a dehydrogenativeintramolecular dehydro Diels Alder reaction in the presence of microwaveirradiation to form a halo substituted naphthalene; and reacting thehalo substituted naphthalene to a cross coupling reaction to form afunctionalized naphthalene having a structure according to Formula I,

where R¹ is a substituent selected from the group consisting of H,C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, phenyl, aryl, heteroaryl, —S(O)R⁴,—S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ where Y is O, NR⁵, or S; each R² is ahalogen or an electron donating group selected from —N(R⁶)₂, —OR⁶, and—SR⁶; each R³ is H, C₁-C₂₀ alkyl, or combined as ═O; each R⁴, R⁵ and R⁶is independently selected from H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy,substituted or unsubstituted phenyl, aryl, heteroaryl, benzyl, or maycome together to form a cyclic structure; X is CH₂, C(R⁶)₂,C(CO₂Alkyl)₂, O, NTs, NH, NCOR⁵ or NR⁵; n is an integer from 0 to 2; mis an integer from 1 to 4, provided that either R¹ is one of —S(O)R⁴,—S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ or the R³ groups are combined as ═O.In these embodiments, the 2′ alkynyl substituted halostyrene may have astructure as shown herein, for example where the alkyl may besubstituted, the tether between the styryl double bond and the alkynemay have substitution and functionality (such as a carbonyl, ether,amine, amide, gem-diester, or alkyl substitution), and the aromatic ringmay be substituted with a chlorine or a variety of other groupsrepresented by R². As described herein the cross coupling reactionconverts the halogen on the halo substituted naphthalene to an electrondonating group, such as a group selected from —N(R⁶)₂, —OR⁶, and —SR⁶.Examples of cross coupling reactions include transition metal mediatedcross coupling reactions, such as a palladium catalyst in theBuchwald-Hartwig reaction.

According to various embodiments of the described methods, thefunctionalized naphthalenes may have a structure where R¹ is —S(O)R⁴,—S(O)₂R⁴, P(O)(OR⁴)₂, or —C(Y)R⁴, Y is O or NR⁵ and R⁴ and R⁵ areindependently H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, phenyl, or aryl, and eachR² is Cl, —N(R⁶)₂, or —OR⁶, where each R⁶ is H, C₁-C₂₀ alkyl,substituted or unsubstituted phenyl, or come together to form a cyclylor heterocyclyl structure having 4-5 carbon atoms. According to specificembodiments of the methods, the functionalized naphthalene may have astructure

According to still other embodiments, the present disclosure providesmethods for fluorescing a fluorescent functionalized naphthalene havinga structure according to any of the embodiments described herein. Forexample, the functionalized naphthalene may have a structure

where R¹ is a substituent selected from the group consisting of H,C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, phenyl, aryl, heteroaryl, —S(O)R⁴,—S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ where Y is O, NR⁵, or S; each R² is ahalogen or an electron donating group selected from —N(R⁶)₂, —OR⁶, and—SR⁶; each R³ is H, C₁-C₂₀ alkyl, or combined as ═O; each R⁴, R⁵ and R⁶is independently selected from H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy,substituted or unsubstituted phenyl, aryl, heteroaryl, benzyl, or maycome together to form a cyclic structure; X is CH₂, C(R⁶)₂,C(CO₂Alkyl)₂, O, NTs, NH, NCOR⁵ or NR⁵; n is an integer from 0 to 2; mis an integer from 1 to 4, provided that either R¹ is one of —S(O)R⁴,—S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ or the R³ groups are combined as ═O.According to the various embodiments of these methods, the method maycomprise the steps of irradiating the functionalized naphthalene withelectromagnetic radiation and measuring the amount of fluorescent lightemitted by the irradiated functionalized naphthalene. In specificembodiments the fluorescent light emitted by the irradiatedfunctionalized naphthalene may have a emission maximum at a wavelengthfrom 450 nm to 650 nm.

In still other embodiments, the functionalized, substituted naphthalenesof the present disclosure may have a structure where the naphthalene hasa group(s) attached either directly or indirectly, for example, via atether, that is capable of forming a bond with another molecule orsubstrate. The bond may be a covalent bond or an ionic bond. Accordingto these embodiments, the other molecule or substrate may be “tagged”with the functionalized naphthalene. For example, according toembodiments where the functionalized naphthalene has fluorescentproperties, the naphthalene may act as a fluorescent tag, wherein thetagged substrate or molecule fluoresces at a wavelength determined bythe presence of the tagging functionalized naphthalene. The taggingnaphthalenes may be used to tag various substrates, such as organiccompounds, inorganic compounds, proteins, enzymes, nucleic acids, othercellular components and the like. According to specific embodiments,functionalized naphthalenes having a group capable of forming a bondwith another substrate may include a carboxylic acid, ester, amide,diol, triazole, thiol, or other known tagging functional groups.Non-limiting examples of substituted naphthalene structures that have afunctional group capable of tagging are illustrated in Scheme 5.

According to various embodiments, the present disclosure providesattachable solvatochromic fluorophores suitable for bioconjugationstudies. The skeletons of the naphthalene fluorophores may be chemicallymodified to include reactive functional groups which have minimal affector alteration of the optical properties of the modified compounds whencompared to the parent dyes. The functionalized fluorophores may becovalently attached to the carboxyl group of a fatty acid, and azido-and thiol-containing amino acids, demonstrating their potential forlabeling biomolecules. As shown in Scheme 6, Functionalization of R¹ in103a with a variety of groups is possible and should afford compoundswith the same photophysical properties as naphthalene were R¹═CH₃ andR²═H. Attachment of functional groups and/or biomolecules to the fivemembered ring, as in 103a′, is also predicted to have little effect onthe photophysical properties because this ring is not conjugated withthe chromophore. Regarding attachment sites for fluorophore 102b, R¹ onthe appended aryl ring may be synthetically appealing. In addition, thearyl ring will have little effect on the absorption and emission maximaof the parent dye. A hydroxyl group was selected as a reactivefunctionality for labeling fluorophores 103a, 103a′ and 103b because ofits synthetic versatility, i.e. nucleophilic substitutions, oxidations,and Mitsunobu reactions, however other functional groups such as amines,carboxylate groups, amides, thiols etc. could also be used.

A microwave-assisted intramolecular DDDA reaction of styrenes 4a, 4b,and 4c afforded cyclopenta[b]naphthalenes 5a, 5b, and 5c in 85%, 47% and92% yield, respectively (Scheme 7). A low yield for the conversion of 4bto 5b was attributed to the bulky tert-butyl group. The resulting arylchlorides 5a, 5b and 5c were subjected to palladium-catalyzedcross-coupling amination conditions to isolate the protectedfluorophores 6a-d in 62%, 58%, 71%, and 35% yield, respectively.Reaction conditions for the conversion of 5c to pyrrolidine 6d were notoptimized. The ketal groups of compounds 6a-c were removed by treatmentwith 1N HCl to afford diols 7a-c in 57%, 96%, and 52% yield,respectively. Tetra-n-butylammonium fluoride (TBAF, 2 equiv) in THF wasused to deprotect the TBS groups of substrate 6d to afford 7c inquantitative yield.

Absorption and emission maxima of 6a-d and 7a-c were measured indichloromethane (DCM) revealing interesting trends. Changes to the amineand ketone groups influences the photophysical properties of thesefluorophores, as evidenced by the emission maxima for 6a (566 nm), 6b(527 nm), and 6d (581 nm). However, variations to the diol moiety hadalmost no effect on the optical properties of these dyes. In fact, theketal derivative 6a, the TBS protected compound 6c, and the free diol 7ashowed almost identical fluorescence emission maxima (566 nm, 564 nm,and 567 nm respectively) and only slight changes in the absorptionmaxima were observed.

The diol group of 7a-c was considered for the fluorescent labeling ofcarboxyl groups. To demonstrate this, the fatty acid derivative 8 wasobtained through a coupling reaction of 7b with 10-undecenoic acid anddicyclohexyl carbodiimide (DCC, Scheme 1). The optical properties offluorophore 8 were found to be comparable to that of substrate 7b withan absorption maximum of 324 nm, emission maximum of 531 nm, and aStokes shift of 207 nm in DCM. This unusual fatty acid derivative 8 isbeing examined for its potential to study membrane structure.

To widen the applicability and to show the versatility of these dyes aslabels for biological targets, efforts turned to the labeling of 103a(Scheme 6). This was accomplished by reacting amide 9 and the lithiumacetylide of alkyne 10 to produce the DDDA precursor 11 in 58% yield(Scheme 8). Subjecting 11 to the DDDA reaction conditions followed by aBuchwald-Hartwig cross-coupling reaction generated the TBS-protectedfluorescent compound 12 in a 53% overall yield. Deprotection of the TBSgroup with TBAF afforded the attachable fluorophore 13 in 91% yield.This synthetic protocol allows for the preparation of additionalfluorophores with tethers of varying lengths and conformational mobilitybetween the carbonyl and the reactive hydroxyl group. With regards tooptical properties, the TBS-protected and hydroxyl derivatives 12 and 13showed absorption and emission maxima in DCM comparable to thoseobserved for fluorophore 102a. The final labeling strategy is depictedas 103b (Scheme 6). Analogs of fluorophore 102b are especiallyattractive because this fluorophore displays an absorption maximum inthe visible region of the electromagnetic spectrum (425 nm).

In a manner entirely analogous to the preparation of other DDDAprecursors described herein, 14a and 14b were prepared, isolated andsubjected to microwave irradiation to produce fluorescent dyes 15a and15b in 30% and 40% yield for the three steps (Scheme 9). These compoundsdisplayed similar optical properties when compared with dye 102b.Solvatochromic properties of fluorescent naphthalenes 7b, 13 and 15b,including bathochromic shift are presented in Table 3.

TABLE 3 Spectroscopic Properties of Fluorophores 7b, 13 and 15b 7b 1315b Solvent λ_(abs) ^(a) λ_(em) ^(b) SS^(c) λ_(abs) ^(a) λ_(em) ^(b)SS^(c) λ_(abs) ^(a) λ_(em) ^(b) SS^(c) Toluene 318 493 175 320 526 206424 504 80 CH₂Cl₂ 320 530 210 325 568 243 427 537 110 DMSO 320 561 241327 598 271 427 574 147 Batho- 68 nm 72 nm 70 nm chromic shift^(a)Absorption maxima in nm. ^(b)Emission maxima in nm. ^(c)Stokes shiftin nm.

According to other embodiments, the present disclosure provides anapproach to the synthesis of unnatural amino acids comprising afunctionalized fluorescent naphthalene moiety. As shown in Scheme 10,unnatural amino acids derived from serine derived amino acid 18 and anazide derived amino acid 21 were prepared and demonstrate fluorescentcompounds. The fluorescent modified unnatural amino acids may be used totag peptide and proteins with a fluorophore as described herein toproduce tagged peptides or proteins that may be monitored in vitro or invivo. The present disclosure also provides for a tagged fluorescentpeptide or protein comprising a residue of an unnatural amino acid.

In still other embodiments, the present disclosure provides forfluorescent fatty acid analogs where one or more fatty acid chains areattached to the fluorescent naphthalene structure. For example, in oneembodiment, a fatty acid residue may be attached to a free hydroxylgroup on the substituted fluorescent naphthalene to form a fatty acidester substituted naphthalene. Alternatively, the fatty acid residue maybe attached to a primary or secondary amine on the naphthalene to form afatty amide residue on the substituted naphthalene. One example of thisapproach is illustrated in Scheme 11.

According to other embodiments, the de novo chemical synthesis andfluorophore design strategy described herein will be used to preparenear infra red-infra red (“NIR-IR”) solvatochromic membrane probes. Fora first generation of compounds, the position of the electron-donatinggroups on the cyclopenta[b]naphthalene ring have been altered and variedthe R group (H, Ph, TMS), for example to include heavy atom groups andNMR active groups, such as silyl (trimethyl silyl, triphenylsilyl,diphenyl methyl and alkoxy silyl groups), phosphorous groups, and NMRactive isotopes such as ¹⁹F, ²H, ¹³C, or ³¹P. In specific embodiments,the substituted naphthalenes may be labeled with an NMR active isotope,such as ¹⁹F, ²H, ¹³C, or ³¹P, and may be used as an NMR probe, forexample as a membrane sensor using NMR to analyze interactions betweenthe active isotope and its surroundings.

In specific embodiments, altering the position of the dimethylaminogroup may lead to a red-shifted emission of from 100 nm to 140 nm ormore. In addition, by changing the R group from a hydrogen to a silyl(trimethylsilyl (TMS)) group or other heavy atom group, such as aphosphorous containing group, the absorption and emission wavelengthsare both been significantly red-shifted (Scheme 12). In addition, theTMS-substituted is the most intensely fluorescent compound in thisseries. For a few of these substrates the Stokes shift was increasedsignificantly, a desired property since this may inhibit self-quenching.Thus, the present disclosure provides substituted naphthalenefluorophores having large Stokes shifts, while maintaining fluorescentintensity. Conventional bright dyes do not typically display largeStokes shifts, so one approach in the art is to connect multiplefluorophores with energy donor-acceptor architectures together so thatcan achieve large pseudo-Stokes shifts, collectively call energytransfer cassettes. In contrast, specific embodiments of the naphthalenefluorophores described herein may show the large Stokes shift and highintensity while having small molecular structures that may be attachedwithout significant change in the molecular environment of the taggedmolecule.

Still other embodiments of the substituted naphthalene fluorophores mayeither absorb or emit in the NIR-IR or both. For these fluorophores, theabsorption spectra has been shifted well into the visible region (442nm) and emission spectra is red-shifted by up to 100 nm when compared toconventional lipid membrane sensor, Laurdan. Thus, fluorophoresdescribed herein may display lower in phototoxicity and may be moreamenable to routine confocal microscopy; whereas conventional Laurdanrequires the use of a more expensive less available two-photonmicroscope. Finally, the solvatochromic dyes described herein maycircumvent issue of FRET biosensors such as they do not require twopartners in close proximity or very specific arrangement.

In other embodiments, the substituted naphthalene fluorophores describedherein may act as a NIR-IR solvatochromic sensor for monitoring membranefunction in living systems, such as those fluorophores that involvestructures with increased aromatic groups on a silicon moiety (such astriphenylsilyl), changing the electron donating group, for example toprimary amines to give higher quantum yields. However, becausereactivity of amines (protonation, oxidation) in general can beproblematic, certain embodiments of the naphthalenes may incorporate analternative electron-releasing/donating group. In other embodiments,solubility of the naphthalene fluorophore may be manipulated, forexample by attaching a polar substituent, such as a carboxylic acid,ammonium salt, sulfonic acid group and the like onto the sensorstructure. According to other embodiment, extending the conjugatedsystem of the fluorophores herein, as it is believed that moreconjugation can lead to shifts to longer wavelengths. For example, incyanine dyes, every methylene that is added to the chromophore componentresults in a wavelength that is red-shifted by 100 nm. Still otherembodiments may include incorporation of rotationally restricted groupson the fluorophores to increase the quantum yields. In otherembodiments, the naphthalene structures may incorporate heterocyclicsubstituents as recognition elements for molecular imaging.

According to certain embodiments, the present disclosure provides for afunctionalized naphthalene fluorophore having a structure: a)1-(5-(dimethylamino)-2′,2′-dimethyl-1,3-dihydrospiro[cyclopenta[b]naphthalene-2,5′-[1,3]dioxan]-9-yl)ethanone;b)1-(5-(dimethylamino)-2′,2′-dimethyl-1,3-dihydrospiro[cyclopenta[b]naphthalene-2,5′-[1,3]dioxan]-9-yl)-2,2-dimethylpropan-1-one;c) 1-(2,2-bis(((tert-butyldimethylsilyl)oxy)methyl)-8-(dimethylamino)-2,3-dihydro-1H-cyclo-penta[b]naphthalen-4-yl)ethanone;d)1-(2′,2′-dimethyl-5-(pyrrolidin-1-yl)-1,3-dihydrospiro[cyclopenta[b]naphthalene-2,5′-[1,3]dioxan]-9-yl)ethanone;e)1-(8-(dimethylamino)-2,2-bis(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone;f)1-(8-(dimethylamino)-2,2-bis(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)-2,2-dimethylpropan-1-one;g)1-(2,2-bis(hydroxymethyl)-8-(pyrrolidin-1-yl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone;h)(8-(dimethylamino)-4-pivaloyl-2,3-dihydro-1H-cyclopenta[b]naphthalene-2,2-diyl)bis(methylene)bis(undec-10-enoate);i)6-((tert-butyldimethylsilyl)oxy)-1-(8-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)hexan-1-one;j)1-(8-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)-6-hydroxyhexan-1-one;k)9-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)-7-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one; 1)7-(dimethylamino)-9-(4-(2-hydroxyethoxy)phenyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;m)9-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-7-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;n)7-(dimethylamino)-9-(4-(hydroxymethyl)phenyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;o)2-(4-(6-dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)dione; p)1-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzyl)-1H-pyrrole-2,5-dione;q) ethyl2-((tert-butoxycarbonyl)amino)-3-((1-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzyl)-2,5-dioxopyrrolidin-3-yl)thio)propanoate;r)4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzaldehyde;s)7-(dimethylamino)-9-(4-ethynylphenyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;t) methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)propanoate;u)4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzylundec-10-enoate; v)5-(Dimethylamino)-9-phenyl-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;w)6-(Dimethylamino)-9-phenyl-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;x)5-(Dimethylamino)-9-(trimethylsilyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;y)6-(Dimethylamino)-9-(trimethylsilyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;z) 5-(Dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one; aa)6-(Dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one; or bb)8-(Dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one.

As described herein, certain embodiments of the substituted naphthalenefluorophores may be attached to an amino acid residue to provide amodified amino acid that may be incorporated into a peptide or aprotein. According to these embodiments, the tagged peptide or proteinmay then be monitored in vivo or in vitro using fluorescent techniques.According to certain embodiments, the present disclosure provides apeptide or protein comprising a modified amino acid residue comprising asubstituted naphthalene fluorophore. According to specific embodiments,the modified amino acid residue is2-(amino)-3-((1-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzyl)-2,5-dioxopyrrolidin-3-yl)thio)propanoateor2-(amino)-3-(4-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)propanoate,which may be derived from the modified amino acid structures set forthherein. The proteins or peptides comprising the modified amino acidresidues may be made using automated synthetic methods, if desired or byother methods known in the art of peptide synthesis.

Still further embodiments of the present disclosure provide for afunctionalized naphthalene fluorophore having a structure:

where R¹ is a substituent selected from the group consisting of H,C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, an NMR active isotope or an alkyl or alkoxygroup comprising an NMR active isotope, a substituted silyl,trialkylsilyl, diphenylalkylsilyl, triphenylalkylsilyl, a substitutedphosphorous, dialkylphosphino, diphenylphosphino, phenyl, aryl,heteroaryl, —S(O)R⁴, —S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ where Y is O,NR⁵, or S; each R² is a halogen, an NMR active isotope or an alkyl oralkoxy group comprising an NMR active isotope, a substituted silyl,trialkylsilyl, diphenylalkylsilyl, triphenylalkylsilyl, a substitutedphosphorous, dialkylphosphino, diphenylphosphino, or an electrondonating group selected from —N(R⁶)₂, —OR⁶, and —SR⁶; each R³ is H,C₁-C₂₀ alkyl, an NMR active isotope or an alkyl or alkoxy groupcomprising an NMR active isotope, a substituted silyl, trialkylsilyl,diphenylalkylsilyl, triphenylalkylsilyl, a substituted phosphorous,dialkylphosphino, diphenylphosphino, or combined as ═O; each R⁴, R⁵ andR⁶ is independently selected from H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, asubstituted silyl, trialkylsilyl, diphenylalkylsilyl,triphenylalkylsilyl, a substituted phosphorous, dialkylphosphino,diphenylphosphino, an NMR active isotope or an alkyl or alkoxy groupcomprising an NMR active isotope, substituted or unsubstituted phenyl,aryl, heteroaryl, benzyl, or may come together to form a cyclicstructure; X is CH₂, C(R⁶)₂, C(CO₂Alkyl)₂, O, NTs, NH, NCOR⁵ or NR⁵; nis an integer from 0 to 2; m is an integer from 1 to 4, provided thateither R¹ is one of —S(O)R⁴, —S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ or the R³groups are combined as ═O.

According to specific embodiments of the functionalized naphthalenefluorophores, at least one of the R¹, R², R³, R⁴, R⁵ or R⁶ groups maycomprise an NMR active isotope or an alkyl or alkoxy group comprising anNMR active isotope, where the NMR active isotope is selected from ²H,¹³C, ¹⁹F, or ³¹P. According to these embodiments, the labeledfluorophores may be used in NMR spectroscopy for real time monitoring ofin vivo or in vitro events, such as events within lipid bilayers andcell membranes.

According to other embodiments of the functionalized naphthalenefluorophores, at least one of the R¹, R², R³, R⁴, R⁵ or R⁶ groups maycomprise a substituted silyl, trialkylsilyl, diphenylalkylsilyl,triphenylalkylsilyl, a substituted phosphorous, dialkylphosphino, ordiphenylphosphino group. As described herein, the presence of heavyatoms, such as, but not limited to, substituted silyl or substitutedphosphorous containing groups on the naphthalene fluorophore structuremay impact the adsorption or emission characteristics of thefluorophore, such as the Stokes shift, the bathochromic shift or thefluorescence intensity, for example.

According to other embodiments of the functionalized naphthalenefluorophores, at least one of the R¹, R², R³, R⁴, R⁵ or R⁶ groups maycomprise a fatty acid residue. Naphthalene fluorophores substituted withlipophilic fatty acid-type long alkyl chains may change the solubilityof the fluorophore and make the fluorophore more soluble in hydrophobicenvironments, such as cell membranes. This, in combination with NMRlabeling may allow for ready monitoring of intramembrane events with thefluorophore compounds recited herein.

Still other embodiments may provide for methods for monitoring a taggedcompound in vivo or in vitro. The method may comprise tagging abiological compound with a functionalized naphthalene fluorophoreaccording to any of the various embodiments describe herein; andmonitoring the tagged compound using a spectroscopic technique. Forexample, in one embodiment the functionalized naphthalene fluorophoremay be tagged with an NMR active isotope or an alkyl or alkoxy groupcomprising an NMR active isotope, where the NMR active isotope isselected from ²H, ¹³C, ¹⁹F, or ³¹P; and monitoring the tagged compoundcomprises monitoring the tagged compound using NMR spectroscopy. Asrecited herein, this may allow for monitoring interactions includingcellular and intramembrane interactions using NMR spectroscopy.According to other embodiments, the functionalized naphthalenefluorophore may comprise an amino acid residue selected from2-(amino)-3-((1-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzyl)-2,5-dioxopyrrolidin-3-yl)thio)propanoateor2-(amino)-3-(4-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)propanoate,and monitoring the tagged compound comprises monitoring the taggedcompound using fluorescent spectroscopy, as detailed herein.

According to various embodiments, the present disclosure may provide fora fluorescent sensor. According to these embodiments, the fluorescentsensor may comprise a functionalized, substituted naphthalene having astructure according to the various embodiments described herein.According to certain embodiments, the fluorescent sensor may comprise afunctionalized, substituted naphthalene having a structure

where R¹ is a substituent selected from the group consisting of H,C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, phenyl, aryl, heteroaryl, —S(O)R⁴,—S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ where Y is O, NR⁵, or S; each R² is ahalogen or an electron donating group selected from —N(R⁶)₂, —OR⁶, and—SR⁶; each R³ is H, C₁-C₂₀ alkyl, or combined as ═O; each R⁴, R⁵ and R⁶is independently selected from H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy,substituted or unsubstituted phenyl, aryl, heteroaryl, benzyl, or maycome together to form a cyclic structure; X is CH₂, C(R⁶)₂,C(CO₂Alkyl)₂, O, NTs, NH, NCOR⁵ or NR⁵; n is an integer from 0 to 2; mis an integer from 1 to 4, provided that either R¹ is one of —S(O)R⁴,—S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ or the R³ groups are combined as ═O.

Still further embodiments of the present disclosure may include asolvatochromic fluorophore. According to these embodiments, thesolvatochromic fluorophore may comprise a functionalized, substitutednaphthalene having a structure according to the various embodimentsdescribed herein. According to certain embodiments, the solvatochromicfluorophore may comprise a functionalized, substituted naphthalenehaving a structure

where R¹ is a substituent selected from the group consisting of H,C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, phenyl, aryl, heteroaryl, —S(O)R⁴,—S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ where Y is O, NR⁵, or S; each R² is ahalogen or an electron donating group selected from —N(R⁶)₂, —OR⁶, and—SR⁶; each R³ is H, C₁-C₂₀ alkyl, or combined as ═O; each R⁴, R⁵ and R⁶is independently selected from H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy,substituted or unsubstituted phenyl, aryl, heteroaryl, benzyl, or maycome together to form a cyclic structure; X is CH₂, C(R⁶)₂,C(CO₂Alkyl)₂, O, NTs, NH, NCOR⁵ or NR⁵; n is an integer from 0 to 2; mis an integer from 1 to 4, provided that either R¹ is one of —S(O)R⁴,—S(O)₂R⁴, P(O)(OR⁴)₂, and —C(Y)R⁴ or the R³ groups are combined as ═O.

According to various embodiments of the fluorescent sensor or thesolvatochromic fluorophore, the sensor or the solvatochromic fluorophoremay have a functionalized, substituted naphthalene structure:

These and other features of the various embodiments of the presentdisclosure will become more apparent upon consideration of the followingexamples. The various embodiments of this disclosure described in thefollowing examples are not to be considered as limiting the invention totheir details.

EXAMPLES General Methods

All commercially available compounds were purchased from AldrichChemical Co., GFS Chemicals, Strem Chemicals, Acros Organics, AlfaAesar, and Advanced Chemtech and used as received, except forp-toluenesulfonyl hydrazide, which was recrystallized from methanol.Amines were purchased from Aldrich Chemical Co. as purified byredistillation and used as received. Tetrahydrofuran (THF), diethylether (Et₂O), and dichloromethane (CH₂Cl₂) were purified by passingthrough alumina using the Sol-Tek ST-002 solvent purification system.Acetonitrile (MeCN) and toluene were freshly distilled from CaH₂ priorto use. Benzene was freshly distilled from sodium/benzophenone prior touse Anhydrous N,N-dimethylformamide (DMF), 1,2-dichloroethane (DCE), and1,4-dioxane were purchased and used as received from Aldrich ChemicalCo. Purification of the compounds by flash column chromatography wasperformed using silica gel (32-63 μm particle size, 60 Å pore size)purchased from Silicycle, or by using a Biotage Horizon flashpurification system with either Biotage SNAP KP-SIL silica cartridges,or Teledyne ISCO RediSep Rf normal phase disposable flash columns (40-60micron). TLC analyses were performed on EMD Chemicals Silica Gel 60 F₂₅₄glass plates (250 μm thickness). ¹H NMR and ¹³C NMR spectra wererecorded on Bruker Avance 300 MHz, 500 MHz, or 600 MHz spectrometers.Spectra were referenced to residual chloroform (7.27 ppm, ¹H, 77.0 ppm,¹³C) or 1,2-dichlorobenzene (6.93 ppm, ¹H, 127.19 ppm, ¹³C). Chemicalshifts are reported in ppm, multiplicities are indicated by s (singlet),d (doublet), t (triplet), q (quartet), p (pentet), and m (multiplet).Coupling constants, J, are reported in hertz (Hz). All NMR spectra wereobtained at room temperature unless otherwise specified. IR spectra wereobtained using a Nicolet Avatar E.S.P. 360 FT-IR. EI mass spectroscopywas performed on a Waters Micromass GCT high resolution massspectrometer. ES mass spectroscopy was performed on a Waters Q-TOFUltima API, Micromass UK Limited high resolution mass spectrometer. GCmass spectrometry was performed on a Shimadzu GCMS-17A/QP5050Aspectrometer. All microwave-mediated reactions were carried out using aBiotage Initiator™ Exp microwave synthesizer. The microwave parameterswere set to variable power, constant temperature, with the fixed holdtime set to on. The microwave reactions were carried out in 0.2-0.5 mL,0.5-2 mL, 2-5 mL, or 10-20 mL Biotage microwave vials. Referenceslocated after compound names refer to literature protocols for how toprepare these or similar compounds by comparable methodology. Absorptionand fluorescence spectra were recorded on Lambda 9 spectrophotometer(Perkin Elmer) and FluoroMax-3 spectrofluorometer (Jobin Yvon, Horiba),respectively. Fluorescence quantum yields were determined by takingProdan in DMSO (quantum yield, QY=91%) as a reference. The quantum yieldvalues were corrected for the solvent refractive index. Forspectroscopic measurements, 10⁻⁵ M solutions of dyes in 10 mmquartz-cuvettes were used (excitation wavelength was 334 nm; slits opento 2 nm).

Synthesis of Functionalized Naphthalenes

Literature Preparation.

The preparation of N,N-dimethylhexa-4,5-dien-amide (S2) followed theprocedure reported by Brummond et al., Org. Lett. 2005, 7, 3473.

Hex-5-ynal (4).

To a one-neck 250 mL round-bottomed flask equipped with a septum piercedwith a needle and a stir bar was added pyridinium chlorochromate (15.6g, 72.6 mmol) and DCM (133 mL) with stirring. 5-Hexyn-1-ol (4.00 mL,36.3 mmol) was added all at once via syringe, and the reaction turneddark brown and thick. The reaction was stirred at rt for 2 h untilcomplete by TLC, followed by addition of Et₂O (100 mL) and silica gel(50 g). The suspension was stirred for 30 min, filtered through a pad ofsilica gel with Et₂O washings, and then concentrated under reducedpressure to yield the aldehyde 4 as a light yellow oil (2.98 g, 85%).The crude product was carried on without further purification. Compound4 was previously characterized.

(E)-Hept-1-en-6-yn-1-ylbenzene (S1)

To a flame-dried two-neck 250 mL round-bottomed flask equipped with areflux condenser, an argon inlet adapter, a septum, and a stir bar wasadded sodium hydride (1.26 g of a 60% dispersion in oil, 31.4 mmol). Theflask was flushed with argon, and THF (38 mL) was added via syringe withstirring. Diethyl benzylphosphonate (6.00 mL, 28.8 mmol) in THF (19 mL)was added dropwise over 10 min via syringe, and the reaction was stirredfor 15 min at rt. Aldehyde 4 (1.26 g, 13.1 mmol) in THF (19 mL) wasadded dropwise over 10 min via syringe, turning the reaction from cloudywhite to yellow. The reaction was heated at reflux for 2 h until it wascomplete by TLC. The reaction turned dark brown in color whilerefluxing. Once the reaction was complete by TLC, it was cooled to rtand quenched with sat'd aq ammonium chloride causing precipitation oftan solids. The aqueous layer was separated and extracted with Et₂O(2×). The combined organic layers were washed with brine, dried overmagnesium sulfate, gravity filtered, and concentrated under reducedpressure to yield a crude yellow oil. The crude product was purified bysilica gel column chromatography (50 g silica cartridge, 0-25% ethylacetate/hexanes) to yield enyne S1 as a colorless oil (1.51 g, 68%).

(E)-13-Phenyltrideca-1,2,12-trien-7-yn-6-one (1)

To a flame-dried two-neck round-bottomed flask equipped with an argoninlet adapter, a septum, and a stir bar was added enyne S1 (0.225 g,1.32 mmol) in THF (3.5 mL). The solution was cooled at −78° C. (bathtemperature) in a dry ice/acetone bath, and n-butyllithium (0.76 mL of a1.6 M solution in hexanes, 1.22 mmol) was added dropwise via syringeturning the reaction purple. The reaction was stirred at −78° C. for 45min, and amide S2 (0.142 g, 1.02 mmol) in THF (3.5 mL) was addeddropwise via syringe turning the reaction yellow. The reaction wasstirred for 5 min, followed by dropwise addition of boron trifluoridediethyl etherate (0.16 mL, 1.28 mmol) via syringe. The reaction wasstirred at −78° C. for 3 h until complete by TLC. Boron trifluoridediethyl etherate (0.16 mL, 1.28 mmol) and acetic acid (70 μL, 1.28 mmol)were added sequentially via syringe. The reaction was then warmed to−20° C. and quenched with sat'd aq ammonium chloride. The aqueous layerwas separated and extracted with Et₂O (2×). The combined organic layerswere washed with brine, dried over magnesium sulfate, gravity filtered,and concentrated under reduced pressure. The crude product was purifiedby silica gel column chromatography (25 g silica cartridge, 0-10% ethylacetate/hexanes) to yield the product 1 as a light yellow oil (197 mg,73%).

1-(2,3-Dihydro-1H-cyclopenta[b]naphthalen-4-yl)hexa-4,5-dien-1-one (2)

To a 2-5 mL MWI vial equipped with a stir bar was added theene-allene-yne 1 (50 mg, 0.19 mmol) in o-dichlorobenzene (2.5 mL), andthe reaction was irradiated with stirring at 225° C. for 10 min untilcomplete by TLC. The reaction was then transferred directly to a silicagel cartridge and purified by silica gel column chromatography (25 gsilica cartridge, 0-3% Et₂O/pentane) to yield 2 as a light yellow oil(34 mg, 68%).

Data for 2 (LSK-2-162)

¹H NMR (400 MHz, CDCl₃) 7.79 (s, 1H), 7.31-7.23 (m, 2H), 7.44-7.42 (m,2H), 5.27 (p, J=7.6 Hz, 1H), 4.71-4.68 (m, 2H), 3.09-3.01 (m, 6H),2.51-2.49 (m, 2H), 2.17 (p, J=7.2 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 208.4, 208.2, 143.1, 139.5, 134.6, 133.0,128.6, 128.1, 125.9, 125.4, 124.0, 89.1, 76.1, 43.5, 32.4, 31.9, 26.2,22.4 ppm

IR (thin film) 3057, 2951, 2829, 2283, 1954, 1693, 1607, 1575 cm⁻¹

LRMS (TOF MS ES+) m/z (%): 263 (100), 246 (14), 245 (52), 206 (10), 205(23), 195 (27), 193 (10), 167 (4)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₉H₁₉O, 263.1436. found, 263.1436.

N′-(1-(2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)hexa-4,5-dien-1-ylidene)-4-methylbenzene-sulfonohydrazide(3)

To a flame-dried one-neck 1 mL flask was added p-toluenesulfonylhydrazide (0.015 g, 0.080 mmol). The flask was equipped with a septumand purged with argon. Naphthalene 2 (0.021 g, 0.080 mmol) in absoluteethanol (0.25 mL) was added all at once with stirring, and the reactionmixture was heated to reflux in an oil bath. Concentrated hydrochloricacid (5 μL, 0.060 mmol) was added, and the reaction became yellow incolor. The reaction remained heating at reflux for 4 h, was let cool tort, and was stirred at rt for 16 h. The reaction mixture was then takenup in DCM and washed with brine (1×). The organic layer was dried overmagnesium sulfate, gravity filtered, and concentrated under reducedpressure to produce a yellow solid. The crude product was purified bysilica gel column chromatography (10 g silica cartridge, 0-10% ethylacetate/hexanes) to yield naphthalene 3 as a white solid (0.016 g, 47%yield). The product still contained some unknown impurity by ¹H NMR.

Data for 3 (LSK-2-170)

¹H NMR (400 MHz, CDCl₃) 7.79 (d, J=8.4 Hz, 1H), 7.75-7.72 (m, 3H), 7.42(t, J=7.4 Hz, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H), 7.10(s, 1H), 6.96 (d, J=7.7 Hz, 1H), 5.11 (p, J=6.6 Hz, 1H), 4.63-4.59 (m,2H), 3.07 (t, J=7.5, Hz, 2H), 2.67-2.62 (m, 2H), 2.59-2.53 (m, 2H), 2.51(s, 3H), 2.33-2.25 (m, 2H), 2.15-2.02 (m, 2H) ppm

General Procedure A Acylation of Alkynes

To a flame-dried two-neck round-bottomed flask equipped with an argoninlet adapter, a septum, and a stir bar was added enyne (1.3 equiv) inTHF (0.40 M). The solution was cooled at −78° C. (bath temperature) in adry ice/acetone bath, and n-butyllithium (1.2 equiv) was added dropwise.The reaction was stirred at −78° C. for 45 min, and amide (1.0 equiv) inTHF (0.30 M) was added dropwise via syringe. The reaction was stirredfor 5 min, followed by dropwise addition of boron trifluoride diethyletherate (1.25 equiv) via syringe. The reaction was stirred at −78° C.until complete by TLC. Boron trifluoride diethyl etherate (1.25 equiv)and acetic acid (1.25 equiv) were added sequentially via syringe. Thereaction was then warmed to −20° C. and quenched with sat'd aq ammoniumchloride. The aqueous layer was separated and extracted with Et₂O (2×).The combined organic layers were washed with brine, dried over magnesiumsulfate, gravity filtered, and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography.

(E)-9-Phenylnon-8-en-3-yn-2-one (5a)

Follows general procedure A: enyne S1 (0.495 g, 2.91 mmol), THF (8 mL),n-butyllithium (1.7 mL of a 1.6 M solution in hexanes, 2.69 mmol),N,N-dimethylacetamide (0.21 mL, 2.24 mmol), THF (8 mL), borontrifluoride diethyl etherate (0.35 mL, 2.80 mmol), and acetic acid (0.16mL, 2.80 mmol). The reaction turned yellow upon addition ofn-butyllithium, and turned orange upon addition of acetic acid. Thereaction was complete after 3 h. The crude product was purified bysilica gel column chromatography (50 g silica cartridge, 0-10% ethylacetate/hexanes) to yield product 5a as a yellow oil (0.329 g, 69%).

1-(2,3-Dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone (6a)

To a 0.5-2 mL microwave irradiation vial equipped with a stir bar wasadded enyne 5a (0.020 g, 0.094 mmol) in DCE (1.6 mL). The reaction wasirradiated with stirring at 180° C. for 30 min until complete by TLC.The reaction turned golden in color. The reaction was then transferredto a vial, concentrated under reduced pressure, and dried under vacuumto yield naphthalene 6a as a black oil (0.020 g, quant.).

Data for 6a (LSK-3-046)

¹H NMR (400 MHz, CDCl₃) 7.82-7.76 (m, 2H), 7.72 (s, 1H), 7.44 (t, J=4.4Hz, 2H), 3.09-3.04 (m, 4H), 2.66 (s, 3H), 2.17 (p, J=7.4 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 206.3, 143.2, 139.8, 134.7, 133.1, 128.4,128.1, 126.0, 125.4, 124.4, 124.2, 32.4, 32.2, 32.1, 26.1 ppm

IR (thin film) 3023, 3060, 2949, 2853, 2210, 1689, 1597, 1499 cm⁻¹

LRMS (TOF MS ES+) m/z (%): 211 (28), 209 (15), 196 (18), 195 (100), 191(83), 169 (12), 167 (6)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₅H₁₅O, 211.1123. found, 211.1154.

(E)-1-Chloro-4-(hept-1-en-6-yn-1-yl)benzene (S3)

(Paquette, L. A. Org. Lett. 2003, 5, 78) To a flame-dried two-neck 100mL round-bottom flask equipped with an argon inlet adapter, a septum,and a stir bar was added diethyl 4-chlorobenzylphosphonate (2.54 mL,11.5 mmol) and THF (29 mL) with stirring. The solution was cooled in anice bath, and n-butyllithium (7.80 mL of a 1.6 M solution in hexanes,12.5 mmol) was added dropwise via syringe over 10 min, turning thereaction brown. After stirring for 30 min, aldehyde 4 (0.500 g, 5.21mmol) in THF (18 mL) was added dropwise via syringe over 10 min. Thereaction was stirred for 30 min in the ice bath, the ice bath wasremoved, and then the reaction was warmed to rt and stirred for 3 h. Thereaction became darker in color. The reaction was slowly quenched withsat'd aq ammonium chloride, causing the solution to become yellow and toprecipitate tan solids. The aqueous layer was separated and extractedwith Et₂O (2×). The combined organic layers were washed with brine,dried over magnesium sulfate, gravity filtered, and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography (25 g silica cartridge, 2-10% ethyl acetate/hexanes) toyield enyne S3 as a yellow oil (0.632 g, 60%).

(E)-9-(4-Chlorophenyl)non-8-en-3-yn-2-one (5b)

Follows general procedure A: enyne S3 (0.904 g, 4.43 mmol), THF (12 mL),n-butyllithium (2.56 mL of a 1.6 M solution in hexanes, 4.09 mmol),N,N-dimethylacetamide (0.32 mL, 3.41 mmol), THF (12 mL), borontrifluoride diethyl etherate (0.53 mL, 4.26 mmol), and acetic acid (0.24mL, 4.26 mmol). The reaction was complete after 3 h. The crude productwas purified by silica gel column chromatography (50 g silica cartridge,0-10% ethyl acetate/hexanes) to yield the product 5b as a yellow oil(0.729 g, 87%).

Data for 5b (LSK-3-053)

¹H NMR (400 MHz, CDCl₃) 7.27 (s, 4H), 6.38 (d, J=15.8 Hz, 1H), 6.16 (dt,J=6.8, 15.8 Hz, 1H), 2.42 (t, J=7.2 Hz, 2H), 2.34 (q, J=7.2 Hz, 2H),2.31 (s, 3H), 1.77 (p, J=7.2 Hz, 2H) ppm

¹³C NMR (125 MHz, CDCl₃) 184.8, 135.9, 132.7, 130.0, 129.7, 128.7 (2C),127.2 (2C), 93.3, 81.8, 32.8, 31.9, 27.2, 18.4 ppm

IR (thin film) 3026, 2936, 2855, 2835, 2210, 1674, 1585, 1490, 1090 cm⁻¹

LRMS (TOF MS ES+) m/z (%): 248 (42), 246 (100), 230 (40), 228 (56), 204(50), 202 (98), 194 (18), 193 (60), 192 (35), 168 (33), 167 (26), 166(15)

HRMS (TOF MS ES+) M+H]⁺ calcd for C₁₅H₁₆OCl, 247.0890. found, 247.0914.

1-(6-Chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone (6b)

To a 2-5 mL microwave irradiation vial equipped with a stir bar wasadded enyne 5b (0.028 g, 0.12 mmol) in DCE (2.1 mL). The reaction wasirradiated with stirring at 180° C. for 200 min until complete by TLC.The reaction turned golden in color. The reaction was then transferredto a vial, concentrated under reduced pressure, and dried under vacuumto yield naphthalene 6b as a brown oil (0.027 g, quant.).

Data for 6b (LSK-3-057)

¹H NMR (300 MHz, CDCl₃) 7.80 (d, J=1.8 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H),7.70 (s, 1H), 7.38 (dd, J=1.8, 9.0 Hz, 1H), 3.07 (t, J=7.1 Hz, 4H), 2.66(s, 3H), 2.18 (p, J=7.1 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 205.4, 143.6, 141.2, 133.8, 131.9, 131.3,129.4, 129.0, 126.3, 124.2, 123.5, 32.4, 32.3, 32.1, 26.1 ppm

IR (thin film) 2952, 2884, 2839, 2206, 1688, 1597, 1489, 1088 cm⁻¹

LRMS (TOF MS EI+) m/z (%): 246 (18), 244 (47), 231 (38), 229 (100), 201(28), 191 (20), 166 (35), 165 (75), 63 (20)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₅H₁₄OCl, 245.0733. found 245.0743.

Literature Preparation.

Diethyl 2-chlorobenzylphosphonate (S4) was prepared from1-(bromomethyl)-2-chlorobenzene and triethyl phosphite via the procedurereported by Luscombe (Doubina, N.; Paniagua, S. A.; Soldatova, A. V.;Jen, A. K. Y.; Marder, S. R.; Luscombe C. K. Macromolecules 2011, 44,512).

1-Chloro-2-(hept-1-en-6-yn-1-yl)benzene (S5)

An oven-dried 250 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with 3-chlorobenzylphosphonate (3.9 g, 15 mmol)and THF (60 mL). The solution was cooled to 0° C. in an ice bath for 15min, then n-BuLi (12 mL of a 1.6 M n-hexane solution, 19 mmol) was addeddropwise over 10 min via syringe. The mixture was stirred at 0° C. for30 min, then aldehyde 4 (1.0 g, 10 mmol) in THF (40 mL) was added. Thesolution was warmed to rt and was stirred for 3 h. The consumption ofthe starting material was monitored by TLC (AcOEt/n-hexane 0.5:9.5). Thereaction was quenched by adding sat'd aq ammonium chloride solution (70mL). The layers were separated and the aqueous phase was extracted withether (3×50 mL). The combined organic layers were washed with brine(2×50 mL), dried over Na₂SO₄, gravity filtered, and concentrated underreduced pressure. The reaction residue was purified by silica gel flashchromatography, eluting with AcOEt/n-hexane 0.5:9.5, to provide 1.11 gof the title compound as a colorless oil in a 54% yield.

9-(2-Chlorophenyl)non-8-en-3-yn-2-one (5c)

An oven-dried 100 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with enyne S5 (1.11 g, 5.4 mmol) and THF (25 mL).The solution was cooled to −78° C. in a dry ice/acetone bath for 15 min,then n-BuLi (3.37 mL of a 1.6 M n-hexane solution, 5.4 mmol) was addedvia syringe. The mixture was stirred at −78° C. for 40 min, thenN,N-dimethylacetamide (0.55 mL, 5.9 mmol) and BF₃.Et₂O (0.74 mL, 5.9mmol) were added. The reaction was stirred at −78° C. for an additional3 h. The consumption of the starting material was monitored by TLC(AcOEt/n-hexane 0.2:9.8). The reaction was quenched by adding sat'd aqammonium chloride solution (35 mL). The layers were separated and theaqueous phase was extracted with ether (3×30 mL). The combined organiclayers were dried over Na₂SO₄, gravity filtered, and concentrated underreduced pressure. The reaction residue was purified by silica gel flashchromatography, eluting with AcOEt/n-hexane 0.2:9.8 to 1:9, to provide0.67 g of the title compound as a yellow oil in a 50% yield.

¹H NMR (400 MHz, CDCl₃) 7.49 (d, J=7.6 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H),7.24-7.10 (m, 2H), 6.80 (d, J=15.7 Hz, 1H), 6.16 (dt, J=15.7, 7.0 Hz,1H), 2.43 (t, J=7.1 Hz, 2H), 2.37 (t, J=7.1 Hz, 2H), 2.33 (s, 3H), 1.79(p, J=7.1 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 184.9, 135.6, 132.7, 132.0, 129.7, 128.3,127.6, 126.9, 126.8, 93.5, 81.9, 32.9, 32.2, 27.2, 18.5 ppm

IR (thin film) 3061, 2933, 2862, 2210, 1647, 1437, 1230 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₅H₁₆ClO, 247.0890. found 247.0874.

1-(8-Chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone (6c)

A microwave irradiation vial (10-20 mL) was equipped with a sir bar (1.5cm) and was charged with compound 5c (0.20 g, 0.81 mmol) and1,2-dichlorobenzene (13.5 mL). The reaction was irradiated with stirringat 180° C. for 3 h, turning gold in color. The solution was directlyadded to a silica gel column, which was eluted with n-hexane to separatethe 1,2-dichlorobenzene and then AcOEt/n-hexane 1:9 to collect the pureproduct. The title compound was isolated as a yellow solid in a 86%yield (0.17 g).

¹H NMR (400 MHz, CDCl₃) 8.19 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.53 (d,J=7.3 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 3.12 (t, J=7.3 Hz, 2H), 3.05 (t,J=7.3 Hz, 2H), 2.64 (s, 3H), 2.19 (p, J=7.3 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 206.0, 144.9, 140.5, 135.2, 132.2, 130.4,129.7, 125.9, 125.8, 123.6, 120.6, 32.8, 32.3, 32.1, 26.2 ppm

IR (thin film) 2952, 1690, 1410, 1350, 1187 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₅H₁₄ClO, 245.0733. found 245.0719.

Literature Preparation.

Diethyl 3-chlorobenzylphosphonate (S6) prepared from1-(bromomethyl)-3-chlorobenzene and triethyl phosphite via the procedurereported by Luscombe.

1-Chloro-3-(hept-1-en-6-yn-1-yl)benzene (S7)

An oven-dried 250 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with 3-chlorobenzylphosphonate S6 (4.74 g, 18mmol) and THF (60 mL). The solution was cooled to 0° C. in an ice bathfor 15 min, then n-BuLi (12 mL of a 1.6 M n-hexane solution, 19 mmol)was added dropwise over 10 min via syringe. The mixture was stirred at0° C. for 30 min, then aldehyde 4 (1.0 g, 10 mmol) in THF (40 mL) wasadded. The reaction was warmed to rt and was stirred for 3 h. Theconsumption of the starting material was monitored by TLC(AcOEt/n-hexane 1:9). The reaction was quenched by adding sat'd aqammonium chloride solution (70 mL). The layers were separated and theaqueous phase was extracted with ether (3×50 mL). The combined organiclayers were washed with brine (2×50 mL), dried over Na₂SO₄, gravityfiltered, and concentrated under reduced pressure. The reaction residuewas purified by silica gel flash chromatography, eluting withAcOEt/n-hexane 0.5:9.5, to provide 1.9 g of the title compound as acolorless oil in a 93% yield.

9-(3-Chlorophenyl)non-8-en-3-yn-2-one (5d)

An oven-dried 100 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with enyne S7 (0.7 g, 3.4 mmol) and THF (40 mL).The solution was cooled to −78° C. in a dry ice/acetone bath for 15 min,then LDA (2 mL of a 2.0 M heptane/THF/ethylbenzene solution, 4.0 mmol)was added via syringe. The mixture was stirred at −78° C. for 1 h, thenN-methoxy-N-methylacetamide (0.4 mL, 3.7 mmol) was added. The solutionwas warmed to rt and was stirred for 4 h. The consumption of thestarting material was monitored by TLC (AcOEt/n-hexane 2:8). Thereaction was quenched by adding sat'd aq ammonium chloride solution (70mL). The layers were separated and the aqueous phase was extracted withether (3×50 mL). The combined organic layers were dried over Na₂SO₄,gravity filtered, and concentrated under reduced pressure. The reactionresidue was purified by silica gel flash chromatography, eluting withAcOEt/n-hexane 1.5:8.5, to provide 0.52 g of the title compound as acolorless oil in a 60% yield.

Data for 5d (EB-026)

¹H NMR (400 MHz, CDCl₃) 7.33 (s, 1H), 7.19 (td, J=7.2, 2.2 Hz, 3H), 6.37(d, J=15.8 Hz, 1H), 6.31-6.04 (m, 1H), 2.42 (t, J=7.1 Hz, 2H), 2.34 (d,J=8.9 Hz, 5H), 1.76 (p, J=7.2 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 184.9, 139.4, 134.6, 130.7, 130.0, 129.9,127.2, 126.0, 124.4, 93.4, 81.9, 32.9, 32.0, 27.3, 18.5 ppm

IR (thin film) 2934, 2210, 1674, 1229, 964 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₅H₁₆ClO, 247.0890. found 247.0886.

1-(7-chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone (6d)and 1-(5-Chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(6d′)

A 10-20 mL microwave irradiation vial was equipped with a sir bar andwas charged with compound 5d (0.2 g, 0.81 mmol) and 1,2-dichlorobenzene(13.5 mL). The reaction was irradiated with stirring at 180° C. for 3 h,turning gold in color. The solution was directly added to a silica gelcolumn, which was eluted with n-hexane to separate the1,2-dichlorobenzene and then AcOEt/n-hexane 1:9 to collect the pureproducts. The title compounds were isolated as a 1.4:1 mixture ofinseparable isomers in a 79% yield.

Data for 6d and 6d′ (EB-028)

¹H NMR (400 MHz, CDCl₃) 7.73-7.58 (m, 2H major isomer and 2H minorisomer), 7.53 (s, 1H major isomer), 7.44 (d, J=7.4 Hz, 1H minor isomer),7.35-7.21 (m, 1H major isomer and 1H minor isomer), 3.02-2.97 (m, 4Hmajor isomer and 4H minor isomer), 2.60 (s, 3H, minor isomer), 2.59 (s,3H, major isomer), 2.14-2.06 (m, 2H major isomer and 2H minor isomer)ppm

¹³C NMR (100 MHz, CDCl₃) 206.7 (minor isomer), 205.5 (major isomer),144.6 (major isomer), 144.0 (major isomer), 141.3 (minor isomer), 140.3(major isomer), 135.1 (major isomer), 134.7 (minor isomer), 134.6 (1Cmajor isomer and 1C minor isomer), 133.9 (major isomer), 131.2 (majorisomer), 129.4 (minor isomer), 127.7 (minor isomer), 127.5 (majorisomer), 126.7 (major isomer), 126.7 (minor isomer), 126.3 (minorisomer), 126.0 (major isomer), 125.4 (minor isomer), 124.0 (minorisomer), 123.4 (major isomer), 33.7 (minor isomer), 32.4 (minor isomer),32.4 (major isomer), 32.2 (major isomer), 32.1 (major isomer), 31.6(minor isomer), 26.1 (major isomer), 25.8 (minor isomer) ppm

IR (thin film) 2949, 1969, 1598, 1418, 1142 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₅H₁₄ClO, 245.0733. found 245.0728.

(E)-1,8-Diphenyloct-7-en-2-yn-1-one (5e)

(Cacchi, S. et al. Org. Lett. 2008, 10, 2629) To a flame-dried two-neck10 mL round-bottomed flask equipped with an argon inlet adapter, aseptum, and a stir bar was added PdCl₂(PPh₃)₂ (0.012 g, 0.017 mmol), THF(3 mL), triethylamine (0.14 mL, 1.03 mmol), and benzoyl chloride (0.12mL, 1.03 mmol). The solution was stirred for 10 min at rt, and copper(I)iodide (0.007 g, 0.034 mmol) was added all at once through the sidearmturning the reaction from cloudy yellow to clear orange. The reactionwas stirred for 10 min, and enyne S1 (0.146 g, 0.86 mmol) in THF (0.5mL) was added all at once via syringe. The reaction was stirred for 3 huntil complete by TLC, in which time the reaction became cloudy andyellow. Water was added to the reaction, and the aqueous layer wasseparated and extracted with ethyl acetate (2×). The combined organiclayers were washed with 1 M hydrochloric acid, sat'd aq ammoniumchloride, and brine, dried over magnesium sulfate, gravity filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography (25 g silica cartridge, 0-10% ethylacetate/hexanes) to yield product 5e as a yellow oil (0.168 g, 71%).

Data for 5e (LSK-3-042)

¹H NMR (400 MHz, CDCl₃) 8.16 (d, J=7.7 Hz, 2H), 7.61 (t, J=7.7 Hz, 1H),7.49 (t, J=7.7 Hz, 2H), 7.36 (d, J=7.7 Hz, 2H), 7.31 (t, J=7.7 Hz, 2H),7.22 (t, J=7.7 Hz, 1H), 6.47 (d, J=15.8 Hz, 1H), 6.22 (dt, J=7.1, 15.8Hz, 1H), 2.58 (t, J=7.2 Hz, 2H), 2.43 (q, J=7.2 Hz, 2H), 1.89 (p, J=7.2Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 178.2, 137.5, 136.9, 134.0, 131.3, 129.6 (2C),128.9, 128.6 (2C), 128.5 (2C), 127.2, 126.1 (2C), 96.3, 80.1, 32.1,27.5, 18.7 ppm

IR (thin film) 3080, 3059, 3025, 2935, 2851, 2234, 2200, 1642, 1596,1579, 1492, 1449, 742 cm⁻¹

LRMS (TOF MS ES+) m/z (%): 275 (65), 274 (35), 257 (100), 258 (29), 242(18), 215 (12)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₀H₁₉O, 275.1436. found, 275.1380.

(2,3-Dihydro-1H-cyclopenta[b]naphthalen-4-yl)(phenyl)methanone (6e)

To a 2-5 mL microwave irradiation vial equipped with a stir bar wasadded enyne 5e (0.050 g, 0.18 mmol) in DCE (3.0 mL). The reaction wasirradiated with stirring at 180° C. for 90 min until complete by TLC.The reaction turned golden in color. The reaction was then transferredto a vial, concentrated under reduced pressure, and dried under vacuumto yield naphthalene 6e as a black oil (0.050 g, quant.).

Data for 6e (LSK-3-050)

¹H NMR (400 MHz, CDCl₃) 7.72 (t, J=8.1 Hz, 2H), 7.79 (s, 1H), 7.58 (d,J=8.1 Hz, 2H), 7.47-7.39 (m, 4H), 7.33 (t, J=8.1 Hz, 1H), 2.98 (t, J=7.4Hz, 2H), 2.70 (t, J=7.4 Hz, 2H), 1.98 (p, J=7.4 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 199.3, 143.1, 141.3, 137.7, 133.7, 133.0,132.3, 130.0, 129.9 (2C), 128.8, 125.8, 125.4, 125.1, 124.0, 32.4, 31.8,26.0 ppm

IR (thin film) 3080, 3059, 3023, 2950, 2835, 1664, 1595, 1448, 749 cm⁻¹

LRMS (TOF MS EI+) m/z (%): 272 (100), 271 (50), 257 (22), 255 (26), 253(22), 167 (19), 165 (50), 152 (20), 105 (15), 77 (20)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₀H₁₇O, 273.1279. found, 273.1301.

(E)-(7-(Methylsulfonyl)hept-1-en-6-yn-1-yl)benzene (5f)

(Saberi, S. P. et al., J. Chem. Soc., Perkin Trans. 11994, 167) To aflame-dried two-neck 25 mL round-bottomed flask equipped with an argoninlet adapter, a septum, and a stir bar was added enyne S1 (0.400 g,2.35 mmol) and THF (5 mL) via syringe. The solution was cooled at −78°C. (bath temperature) in a dry ice/acetone bath, and n-butyllithium(1.53 mL, 2.44 mmol) was added dropwise via syringe turning the reactionpink. The reaction was stirred at −78° C. for 1 h, and methanesulfonylchloride (0.19 mL, 2.40 mmol) was added dropwise via syringe turning thereaction yellow. The reaction was stirred at −78° C. for 45 min, and wasthen warmed to rt and stirred for 1 h. The reaction was quenched withsat'd aq ammonium chloride, and the aqueous layer was separated. Theaqueous layer was extracted with Et₂O (5×), and the combined organiclayers were washed with brine, dried over magnesium sulfate, gravityfiltered, and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography (50 g silica cartridge,0-30% ethyl acetate/hexanes) to yield product 5f as a colorless oil(0.101 g, 17%).

Data for 5f (LSK-3-013)

¹H NMR (400 MHz, CDCl₃) 7.36 (d, J=7.1 Hz, 2H), 7.31 (t, J=7.1 Hz, 2H),7.23 (t, J=7.1 Hz, 1H), 6.44 (d, J=15.7 Hz, 1H), 6.16 (dt, J=7.4, 15.7Hz, 1H), 3.18 (s, 3H), 2.48 (t, J=7.4 Hz, 2H), 2.35 (q, J=7.4 Hz, 2H),1.82 (p, J=7.4 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 137.2, 131.6, 128.6 (2C), 128.3, 127.3, 126.1(2C), 95.2, 77.7, 46.7, 31.9, 26.6, 18.2 ppm

IR (thin film) 3084, 3043, 3024, 2925, 2847, 2200, 1596, 1492, 1320,1147, 771 cm⁻¹

LRMS (TOF MS ES+) m/z (%): 250 (10), 249 (100), 231 (20), 219 (36), 186(22), 185 (36), 168 (22)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₄H₁₇O₂S, 249.0949. found, 249.0939.

4-(Methylsulfonyl)-2,3-dihydro-1H-cyclopenta[b]naphthalene (6f)

To a 2-5 mL microwave irradiation vial equipped with a stir bar wasadded enyne 5f (0.050 g, 0.20 mmol) in o-dichlorobenzene (2.3 mL). Thereaction was irradiated with stirring at 225° C. for 20 min untilcomplete by TLC. The reaction turned golden in color. The crude productwas purified by silica gel column chromatography (14 g silica cartridge,0-15% ethyl acetate/hexanes) to yield naphthalene 6f as a colorless oil(0.038 g, 78%).

Data for 6f (LSK-3-019)

¹H NMR (400 MHz, CDCl₃) 8.86 (d, J=8.8 Hz, 1H), 7.92 (s, 1H), 7.85 (d,J=8.0 Hz, 1H), 7.61 (t, J=8.4 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 3.62 (t,J=7.4 Hz, 2H), 3.21 (s, 3H), 3.08 (t, J=7.4 Hz, 2H), 2.16 (p, J=7.4 Hz,2H) ppm

¹³C NMR (100 MHz, CDCl₃) 147.7, 144.2, 133.8, 130.4, 129.0, 128.8,128.7, 127.5, 126.0, 124.1, 44.7, 34.6, 32.2, 25.6 ppm

IR (thin film) 3015, 2957, 2933, 2876, 2839, 1607, 1495, 1302, 1134 cm⁻¹

LRMS (TOF MS ES+) m/z (%): 247 (100), 246 (28), 168 (75), 166 (15)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₄H₁₅O₂S, 247.0793. found, 247.0762.

(E)-(7-(4-Chlorophenyl)hept-6-en-1-yn-1-yl)(phenyl)sulfane (S8)

(Corlay, H. et al. Tetrahedron 1995, 51, 3303.) To a flame-driedtwo-neck 50 mL round-bottomed flask equipped with an argon inletadapter, a septum, and a stir bar was added enyne S3 (0.465 g, 2.23mmol) in THF (21 mL). The solution was cooled at −78° C. (bathtemperature) in a dry ice/acetone bath and n-butyllithium (1.68 mL of a1.6 M solution in hexanes, 2.68 mmol) was added dropwise via syringeturning the reaction yellow. The reaction was stirred at −78° C. for 1h, and then diphenyl disulfide (0.681 g, 3.12 mmol) in THF (5.5 mL) wasadded dropwise via syringe turning the reaction colorless. The reactionwas stirred at −78° C. for 30 min, and then was warmed to rt and stirredfor 3 h turning the reaction yellow. The reaction was diluted with waterand the layers were separated. The aqueous layer was extracted with Et₂O(3×), and the combined organic layers were washed with brine, dried overmagnesium sulfate, gravity filtered, and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography (40 g silica cartridge, pentane) to yield sulfide S8 as ayellow oil (0.636 g, 91%).

(E)-1-Chloro-4-(7-(phenylsulfonyl)hept-1-en-6-yn-1-yl)benzene (5 g)

(Trost, B. M.; Curran, D. P. Tet. Lett. 1981, 22, 1287) To ascintillation vial equipped with a stir bar was added sulfide S8 (0.139g, 0.45 mmol) in methanol (1.6 mL) and THF (1.6 mL). The solution wascooled in an ice bath, and oxone (0.479 g, 3.15 mmol) in water (1.6 mL)was added dropwise via pipette with vigorous stirring causing thereaction to turn white and cloudy. The reaction was stirred at rt for 3days, and was then diluted with water (3 mL). The aqueous layer wasseparated and extracted with DCM (3×). The combined organic layers werewashed with brine, dried over magnesium sulfate, gravity filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography (4 g silica cartridge, 0-50% ethylacetate/hexanes) to yield sulfone 5 g as a pink oil (45 mg, 29%).

Data for 5g (LSK-3-185)

¹H NMR (300 MHz, CDCl₃) 8.02 (dd, J=7.6, 1.4 Hz, 2H), 7.69 (dt, J=7.4,1.0 Hz, 1H), 7.59 (t, J=7.8 Hz, 2H), 7.29 (m, 4H), 6.32 (d, J=15.8 Hz,1H), 6.08 (dt, J=7.0, 15.8 Hz, 1H), 2.43 (t, J=7.1 Hz, 2H), 2.28 (q,J=7.1 Hz, 2H), 1.75 (p, J=7.1 Hz, 2H) ppm

¹³C NMR (125 MHz, CDCl₃) 142.1, 135.8, 134.0, 132.8, 130.4, 129.3 (2C),129.0, 128.7 (2C), 127.2 (2C), 127.2 (2C), 97.2, 78.7, 31.8, 26.4, 18.3ppm

IR (thin film) 3063, 3023, 2933, 2868, 2200, 1585, 1489, 1328, 1160,756, 728 cm⁻¹

LRMS (TOF MS ES+) m/z (%): 346 (60), 316 (55), 282 (74), 220 (75), 203(100)

HRMS (TOF MS ES+) [M−H]⁺ calcd for C₁₉H₁₆O₂SCl, 343.0560. found,343.0562.

6-Chloro-4-(phenylsulfonyl)-2,3-dihydro-1H-cyclopenta[b]naphthalene (6g)

To a 2-5 mL microwave irradiation vial equipped with a stir bar wasadded enyne 5g (0.045 g, 0.13 mmol) in DCE (2.2 mL). The reaction wasirradiated with stirring at 180° C. for 15 min until complete by TLC.The reaction turned light yellow in color. The reaction was thentransferred to a vial, concentrated under reduced pressure, and driedunder vacuum to yield naphthalene 6g as a white solid (0.040 g, 89%).

Data for 6g (LSK-3-204)

MP Decomposes at 140° C.

¹H NMR (300 MHz, CDCl₃) 8.94 (s, 1H), 7.93 (d, J=7.7 Hz, 2H), 7.85 (s,1H), 7.70 (d, J=8.6 Hz, 1H), 7.55-7.46 (m, 3H), 7.40 (dd, J=1.9, 8.6 Hz,1H), 3.68 (t, J=7.5 Hz, 2H), 3.08 (t, J=7.5 Hz, 2H), 2.18 (p, J=7.5 Hz,2H) ppm

¹³C NMR (100 MHz, CDCl₃) 149.3, 144.5, 142.8, 133.3, 133.0, 132.0,129.7, 129.7, 129.4, 129.1 (2C), 128.9, 126.8, 126.4 (2C), 123.7, 35.1,32.1, 25.5 ppm

IR (thin film) 3065, 2961, 2921, 2859, 1623, 1599, 1487, 1305, 1154,754, 719 cm⁻¹

LRMS (TOF MSMS ES+) m/z (%): 342 (100), 307 (12), 265 (18), 243 (75),202 (45), 200 (25)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₉H₁₆O₂SCl, 343.0560. found,343.0548.

(E)-1-Chloro-4-(7-(phenylsulfinyl)hept-1-en-6-yn-1-yl)benzene (5h)

To a scintillation vial equipped with a stir bar was added sulfide S8(0.075 g, 0.24 mmol) in methanol (0.85 mL) and THF (0.85 mL). Thesolution was cooled in an ice bath, and oxone (0.110 g, 0.72 mmol) inwater (0.85 mL) was added dropwise via pipette with vigorous stirringcausing the reaction to turn white and cloudy. The reaction was stirredat rt for 13 h, and was then diluted with water (2 mL). The aqueouslayer was separated and extracted with DCM (3×). The combined organiclayers were washed with brine, dried over magnesium sulfate, gravityfiltered, and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography (10 g silica cartridge,0-50% ethyl acetate/hexanes) to yield sulfoxide 5h as a colorless oil(38 mg, 48%).

Data for 5 h (LSK-3-186)

¹H NMR (300 MHz, CDCl₃) 7.83-7.80 (m, 2H), 7.58-7.54 (m, 3H), 7.26 (s,4H), 6.33 (d, J=16.0 Hz, 1H), 6.11 (dt, J=6.8, 16.0 Hz, 1H), 2.49 (t,J=7.0 Hz, 2H), 2.30 (q, J=7.0 Hz, 2H), 1.76 (p, J=7.0 Hz, 2H) ppm

¹³C NMR (125 MHz, CDCl₃) 144.4, 135.9, 132.7, 131.6, 130.1, 129.5 (2C),129.5 (2C), 128.7 (2C), 127.2 (2C), 124.9 (2C), 105.4, 78.9, 31.8, 27.0,19.2 ppm

IR (thin film) 3057, 3025, 2932, 2862, 2180, 1646, 1593, 1489, 1088,800, 749 cm⁻¹

LRMS (TOF MSMS ES+) m/z (%): 327 (55), 310 (100), 275 (12)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₉H₁₈OSCl, 329.0767. found,329.0745.

6-Chloro-4-(phenylsulfinyl)-2,3-dihydro-1H-cyclopenta[b]naphthalene (6h)

To a 0.5-2 mL microwave irradiation vial equipped with a stir bar wasadded enyne 5h (0.036 g, 0.11 mmol) in DCE (1.8 mL). The reaction wasirradiated with stirring at 180° C. for 60 min until complete by TLC.The reaction turned golden in color. The reaction was then transferredto a vial, concentrated under reduced pressure, and dried under vacuumto yield naphthalene xx as a golden oil (0.027 g, 75%).

Data for 6h (LSK-3-190)

¹H NMR (300 MHz, CDCl₃) 8.60 (s, 1H), 7.76 (s, 1H), 7.72 (d, J=8.7 Hz,1H), 7.56-7.54 (m, 2H), 7.47-7.37 (m, 4H), 3.52-3.41 (m, 1H), 3.17-3.09(m, 1H), 3.04 (t, J=7.5 Hz, 2H), 2.23-2.11 (m, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 147.5, 144.4, 143.9, 132.5, 132.3, 132.0,130.6, 130.0, 129.7, 129.0 (2C), 126.8, 126.7, 124.3 (2C), 122.7, 31.9,31.5, 25.8 ppm

IR (thin film) 3057, 2949, 2921, 2847, 1595, 1487, 1441, 1084, 1043, 746cm⁻¹

LRMS (TOF MS ES+) m/z (%): 327 (100), 309 (50)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₉H₁₆OSCl, 327.0610. found,327.0617.

(E)-Diethyl (7-(4-chlorophenyl)hept-6-en-1-yn-1-yl)phosphonate (5i)

(Knierzinger, A. et al. Helv. Chim. Acta 1991, 74, 517.) To aflame-dried two-neck 5 mL round-bottomed flask equipped with an argoninlet adapter, a septum, and a stir bar was added enyne S3 (0.150 g,0.74 mmol) in THF (2.5 mL). The solution was cooled at −78° C. (bathtemperature) in a dry ice/acetone bath and n-butyllithium (0.69 mL of a1.6 M solution in hexanes, 1.10 mmol) was added dropwise via syringeturning the reaction amber. The reaction was stirred at −78° C. for 1.5h, and then diethyl chlorophosphate (0.13 mL, 0.89 mmol) was addeddropwise via syringe turning the reaction golden. The reaction wasstirred at −78° C. for 1 h, and then was warmed to −20° C. and pouredinto sat'd aq ammonium chloride solution (5 mL). The aqueous layer wasseparated and extracted with Et₂O (2×). The combined organic layers werewashed with brine, dried over magnesium sulfate, gravity filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography (10 g silica cartridge, 0-80% ethylacetate/hexanes) to yield product 5i as a yellow oil (0.056 g, 22%).

Data for 5i (LSK-4-001)

¹H NMR (300 MHz, CDCl₃) 7.27 (s, 4H), 6.38 (d, J=15.9 Hz, 1H), 6.14 (dt,J=7.0, 15.9 Hz, 1H), 4.16 (p, J=7.3 Hz, 4H), 2.41 (q, J=7.3 Hz, 2H),2.34 (q, J=7.3 Hz, 2H), 1.78 (p, J=7.3 Hz, 2H), 1.38 (t, J=7.1 Hz, 6H)ppm

¹³C NMR (100 MHz, CDCl₃) 135.8, 132.6, 130.0, 129.4, 128.6 (2C), 127.2(2C), 102.3 (d, J=53.0 Hz), 70.9 (d, J=301 Hz), 62.9 (d, J=5 Hz), 31.8,26.9 (d, J=5 Hz), 18.6 (d, J=4 Hz), 16.0 (d, J=8 Hz) ppm

IR (thin film) 2983, 2934, 2896, 2203, 1650, 1489, 1263, 1026, 751 cm⁻¹

LRMS (TOF MS ES+) m/z (%): 341 (100), 283 (12), 203 (38), 155 (21)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₇H₂₃O₃PCl, 341.1073. found,341.1078.

Diethyl(6-chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)phosphonate(6i)

To a 0.5-2 mL microwave irradiation vial equipped with a stir bar wasadded enyne 5i (0.034 g, 0.10 mmol) in o-dichlorobenzene (1.7 mL). Thereaction was irradiated with stirring at 225° C. for 150 min untilcomplete by TLC. The reaction turned golden in color. The reaction wasthen transferred to a vial, concentrated under reduced pressure, anddried under vacuum to yield naphthalene 6i as an amber oil (0.034 g,quant.).

Data for 6i (LSK-4-010)

¹H NMR (300 MHz, CDCl₃) 8.85 (s, 1H), 7.80 (s, 1H), 7.70 (dd, J=2.1, 8.7Hz, 1H), 7.40 (dd, J=2.1, 8.7 Hz, 1H), 4.29-4.00 (m, 4H), 3.48 (dt,J=2.5, 7.1 Hz, 2H), 3.04 (t, J=7.1 Hz, 2H), 2.13 (p, J=7.1 Hz, 2H), 1.33(t, J=6.9 Hz, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) 153.6 (d, J=11 Hz), 143.6 (d, J=16 Hz), 133.6(d, J=13 Hz), 132.3, 131.2 (d, J=12 Hz), 130.5, 129.4, 127.7, 127.4 (d,J=3 Hz), 126.2, 125.8 (d, J=3 Hz), 61.8 (d, J=5 Hz), 35.2, 32.3, 25.6,16.3 (d, J=6 Hz) ppm

IR (thin film) 3080, 2979, 2900, 1621, 1598, 1488, 1238 cm⁻¹

LRMS (TOF MS ES+) m/z (%): 339 (100), 338 (95), 311 (73), 303 (65), 283(72)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₇H₂₁O₃PCl, 339.0917. found,339.0928.

(E)-8-(4-Chlorophenyl)oct-7-en-2-ynal (5j)

To a flame-dried two-neck 10 mL round-bottomed flask equipped with anargon inlet adapter, a septum, and a stir bar was added enyne S3 (0.203g, 1.00 mmol) and THF (2.7 mL) via syringe. The solution was cooled at−78° C. (bath temperature) in a dry ice/acetone bath, and n-butyllithium(0.63 mL, 1.00 mmol) was added dropwise via syringe turning the reactionbrown. The reaction was stirred at −78° C. for 30 min, andN,N-dimethylformamide (0.15 mL, 2.00 mmol) was added dropwise viasyringe turning the reaction colorless. The reaction was stirred at −78°C. for 30 min, and was then warmed to rt and stirred for 2 h. Thereaction was added to a cold solution of ethyl acetate (3 mL) and 10%KH₂PO₄ (6 mL) and stirred for 30 min. The aqueous layer was separatedand the organic layer was washed with brine, dried over magnesiumsulfate, gravity filtered, and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography (10 gsilica cartridge, 0-10% ethyl acetate/hexanes) to yield product 5j as acolorless oil (0.128 g, 55%).

Data for 5j (LSK-4-028)

¹H NMR (300 MHz, CDCl₃) 9.19 (s, 1H), 7.27 (s, 4H), 6.39 (d, J=15.9 Hz,1H), 6.15 (dt, J=6.6, 15.9 Hz, 1H), 2.48 (t, J=6.9 Hz, 2H), 2.35 (q,J=7.2 Hz, 2H), 1.80 (p, J=7.2 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 177.0, 135.8, 132.5, 129.9, 129.4, 128.5,127.1, 98.4, 81.9, 31.7, 26.9, 18.4 ppm

6-Chloro-2,3-dihydro-1H-cyclopenta[b]naphthalene-4-carbaldehyde (6j)

To a 2-5 mL microwave irradiation vial equipped with a stir bar wasadded enyne 5j (0.035 g, 0.15 mmol) in DCE (2.5 mL). The reaction wasirradiated with stirring at 180° C. for 45 min until complete by TLC.The reaction turned golden in color. The reaction was then transferredto a vial, concentrated under reduced pressure, and dried under vacuumto yield naphthalene 6j as a golden sticky solid (0.029 g, 83%).

Data for 6j (LSK-4-015)

¹H NMR (300 MHz, CDCl₃) 10.75 (s, 1H), 9.19 (s, 1H), 7.87 (s, 1H), 7.73(d, J=8.4 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 3.47 (t, J=7.2 Hz, 2H), 3.08(q, J=6.6 Hz, 2H), 2.25 (p, J=7.2 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 192.0, 153.4, 143.9, 134.2, 131.5, 130.6,129.3, 128.7, 127.2, 126.8, 124.6, 123.9, 31.7, 31.4, 25.7 ppm

(E)-Methyl 8-phenyloct-7-en-2-ynoate (5k)

(Michaelides, I. N.; Darses, B.; Dixon, D. J. Org. Lett. 2011, 13, 664.)To a flame-dried two-neck 10 mL round-bottomed flask equipped with anargon inlet adapter, a septum, and a stir bar was added enyne S1 (0.250g, 1.47 mmol) and THF (3 mL) via syringe. The solution was cooled at−78° C. (bath temperature) in a dry ice/acetone bath, and n-butyllithium(1.0 mL of a 1.6 M solution in hexanes, 1.62 mmol) was added dropwiseturning the reaction purple. The reaction was stirred at −78° C. for 45min, then methyl chloroformate (0.15 mL, 1.91 mmol) was added dropwisevia syringe turning the reaction yellow. The reaction was stirred for 1h at −78° C., then warmed to rt over 3 h. The reaction was quenched withsat'd aq ammonium chloride, and the aqueous layer was separated. Theaqueous layer was extracted with Et₂O (2×), and the combined organiclayers were washed with brine, dried over magnesium sulfate, gravityfiltered, and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography (25 g silica cartridge,2-10% ethyl acetate/hexanes) to yield product 5k as a colorless oil(0.263 g, 79%).

Data for 5k (LSK-3-052)

¹H NMR (400 MHz, CDCl₃) 7.34 (t, J=7.6 Hz, 2H), 7.30 (d, J=7.6 Hz, 2H),7.21 (t, J=7.6 Hz, 1H), 6.44 (d, J=16.1 Hz, 1H), 6.18 (dt, J=7.1, 16.1Hz, 1H), 3.78 (s, 3H), 2.40 (t, J=7.2 Hz, 2H), 2.35 (q, J=7.2 Hz, 2H),1.78 (p, J=7.2 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 154.2, 137.5, 131.2, 128.9, 128.6 (2C), 127.1,126.1 (2C), 89.4, 73.3, 52.6, 31.9, 27.1, 18.1 ppm

IR (thin film) 3084, 3051, 3025, 2949, 2863, 2831, 2235, 1712, 1597,1492, 1254, 748 cm⁻¹

LRMS (TOF MS ES+) m/z (%): 229 (93), 228 (15), 227 (10), 197 (41), 196(51), 170 (27), 169 (100)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₅H₁₇O₂, 229.1229. found, 229.1228.

Methyl 2,3-dihydro-1H-cyclopenta[b]naphthalene-4-carboxylate (6k)

To a 10-20 mL microwave irradiation vial equipped with a stir bar wasadded enyne 5k (0.150 g, 0.66 mmol) in o-dichlorobenzene (11 mL). Thereaction was irradiated with stirring at 225° C. for 90 min untilcomplete by TLC. The reaction turned golden in color. The reaction wasthen transferred to a vial and concentrated under high vacuum to yieldnaphthalene 6k as a black oil (0.144 g, 97%).

Data for 6k (LSK-3-087)

¹H NMR (300 MHz, CDCl₃) 8.24 (d, J=8.2 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H),7.77 (s, 1H), 7.46 (dp, J=1.3, 8.2 Hz, 2H), 4.03 (s, 3H), 3.21 (t, J=7.4Hz, 2H), 3.08 (dt, J=1.0, 7.4 Hz, 2H), 2.15 (p, J=7.4 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 169.2, 144.9, 143.0, 133.1, 129.9, 127.9,126.2, 125.7, 125.4, 125.1, 124.6, 51.9, 33.4, 32.6, 25.8 ppm

IR (thin film) 3051, 3002, 2950, 2835, 1609, 1716, 1228 cm⁻¹

LRMS (TOF MS EI+) m/z (%): 227 (5), 195 (10), 166 (22), 83 (100), 82(74), 70 (65), 62 (61)

HRMS (TOF MS ES+) [M] calcd for C₁₅H₁₄O₂, 226.0994. found, 226.0998.

Literature Preparation.

The preparation of hept-6-yn-1-ol (S10) from hept-3-yn-1-ol (S9)followed the procedure reported by Curran, et al. J. Org. Chem. 2010,75, 2942.

Hept-6-ynal (S11)

To a one-neck 50 mL round-bottomed flask equipped with a septum piercedwith a needle and a stir bar, was added pyridinium chlorochromate (2.31g, 10.7 mmol) and DCM (20 mL) with stirring. Alcohol S10 (0.600 g, 5.35mmol) was added all at once via syringe, and the reaction turned darkbrown and thick. The reaction was stirred at rt for 3.5 h until completeby TLC, followed by addition of Et₂O (25 mL) and silica gel (10 g). Thesuspension was stirred for 30 min, filtered through a pad of silica gelwith Et₂O washings, and then concentrated under reduced pressure toyield the aldehyde xx as a yellow oil (0.478 g, 81%). The crude productwas carried on without further purification. Compound S11 was previouslycharacterized.

(E)-Oct-1-en-7-yn-1-ylbenzene (S12)

To a flame-dried two-neck 25 mL round-bottomed flask equipped with areflux condenser, an argon inlet adapter, a septum, and a stir bar wasadded sodium hydride (0.399 g of a 60% dispersion in oil, 9.98 mmol).The flask was flushed with argon, and THF (12 mL) was added via syringewith stirring. Diethyl benzylphosphonate (1.90 mL, 9.11 mmol) in THF (6mL) was added dropwise over 5 min via syringe, and the reaction wasstirred for 15 min at rt. Aldehyde S11 (0.478 g, 4.34 mmol) in THF (6mL) was added dropwise over 5 min via syringe, turning the reaction fromcloudy white to light yellow. The reaction was heated at reflux for 4 huntil it was complete by TLC. The reaction turned dark brown in colorwhile refluxing. Once the reaction was complete by TLC, it was cooled tort and quenched with sat'd aq ammonium chloride causing precipitation oftan solids. The aqueous layer was separated and extracted with Et₂O(2×). The combined organic layers were washed with brine, dried overmagnesium sulfate, gravity filtered, and concentrated under reducedpressure to yield a crude yellow oil. The crude product was purified bysilica gel column chromatography (25 g silica cartridge, 0-25% ethylacetate/hexanes) to yield enyne S12 as a yellow oil (0.157 g, 20%).

(E)-10-Phenyldec-9-en-3-yn-2-one (5l)

Follows general procedure A: enyne S12 (0.132 g, 0.72 mmol), THF (2 mL),n-butyllithium (0.41 mL of a 1.6 M solution in hexanes, 0.66 mmol),N,N-dimethylacetamide (56 μL, 0.60 mmol), THF (2 mL), boron trifluoridediethyl etherate (0.1 mL, 0.75 mmol), and acetic acid (43 μL, 0.75mmol). The reaction was complete after 3 h. After addition of the amidethe reaction turned yellow. The crude product was purified by silica gelcolumn chromatography (10 g silica cartridge, 0-10% ethylacetate/hexanes) to yield the product 5l as a colorless oil (0.093 g,68%).

Data for 5l (LSK-3-123)

¹H NMR (300 MHz, CDCl₃) 7.37-7.30 (m, 4H), 7.21 (t, J=7.0 Hz, 1H), 6.41(d, J=15.9 Hz, 1H), 6.20 (dt, J=6.7, 15.9 Hz, 1H), 2.40 (t, J=6.4 Hz,2H), 2.33 (s, 3H), 2.26 (q, J=6.6 Hz, 2H), 1.70-1.58 (m, 4H) ppm

¹³C NMR (100 MHz, CDCl₃) 185.0, 137.6, 130.4, 130.1, 128.5 (2C), 127.0,126.0 (2C), 93.8, 81.6, 32.8, 32.4, 28.5, 27.2, 18.8 ppm

IR (thin film) 3085, 3056, 3025, 2935, 2859, 2210, 1674, 1598, 1493, 745cm⁻¹

LRMS (TOF MS ES+) m/z (%): 227 (100), 226 (52), 211 (10), 209 (12), 183(9)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₆H₁₉O, 227.1436. found, 227.1420.

1-(1,2,3,4-Tetrahydroanthracen-9-yl)ethanone (6l)

To a 10 mL microwave irradiation vial equipped with a stir bar was addedenyne 51 (0.042 g, 0.19 mmol) in o-dichlorobenzene (3.1 mL). Thereaction was irradiated with stirring at 300° C. for 50 min in an AntonParr Monowave 300 microwave reactor until complete by TLC. The reactionturned light brown in color. The reaction was then transferred to a vialand concentrated under high vacuum to yield naphthalene 6l as a brownoil (0.044 g, quant.).

Data for 6l (LSK-3-141)

¹H NMR (300 MHz, CDCl₃) 7.78-7.73 (m, 1H), 7.59 (s, 1H), 7.56-7.52 (m,1H), 7.44-7.38 (m, 2H), 3.02-3.98 (m, 2H), 2.86-2.82 (m, 2H), 2.63 (s,3H), 1.90-1.86 (m, 4H) ppm

¹³C NMR (100 MHz, CDCl₃) 209.0, 138.7, 135.9, 131.8, 130.5, 127.8,127.6, 127.3, 125.9, 125.4, 123.6, 32.9, 30.1, 27.0, 23.0, 22.8 ppm

IR (thin film) 3055, 2933, 2859, 2831, 1698, 1596, 1498 cm⁻¹

LRMS (ASAP MSMS) m/z (%): 224 (100), 225 (81), 210 (12), 209 (49)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₆H₁₇O, 225.1279. found, 225.1282.

Literature Preparation.

Diethyl 2-(prop-2-yn-1-yl)malonate (S13) was prepared from triethylmethanetricarboxylate through a procedure previously reported byBrummond et al., J. Am. Chem. Soc. 2002, 124, 15186.(E)-1-(3-Bromoprop-1-en-1-yl)-2-chlorobenzene (S14) was prepared from2-chlorobenzaldehyde via the procedure reported by Fering a, et al. Adv.Synth. Catal. 2004, 346, 413.

Diethyl 2-(3-(2-chlorophenyl)allyl)-2-(prop-2-yn-1-yl)malonate (S15)

An oven-dried, 100 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with diethyl 2-(prop-2-yn-1-yl)malonate S13 (1.8g, 9.1 mmol), (E)-1-(3-bromoprop-1-en-1-yl)-2-chlorobenzene S14 (2.1 g,11.0 mmol), and THF (60 mL). The solution was cooled to 0° C. in an icebath for 15 min, then NaH (0.43 g of a 60% dispersion in mineral oil,11.0 mmol) was added in one portion. The solution was stirred at 0° C.for 2 h. The consumption of the starting material was monitored by TLC(AcOEt/n-hexane 0.5:9.5). The reaction was then quenched with sat'd aqammonium chloride solution (70 mL). The layers were separated and theaqueous phase was extracted with AcOEt (3×50 mL). The combined organiclayers were dried over Na₂SO₄, gravity filtered, and concentrated underreduced pressure. The reaction residue was purified by silica gel flashchromatography, eluting with AcOEt/n-hexane 0.5:9.5, to provide 2.55 gof the title compound as a yellow oil in 81% yield.

Diethyl 2-(3-(2-chlorophenyl)allyl)-2-(4-oxopent-2-yn-1-yl)malonate (5m)

An oven-dried 100 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with compound enyne S15 (0.5 g, 1.4 mmol) and THF(20 mL). The solution was cooled to −78° C. in a dry ice/acetone bathfor 15 min, then LDA (0.7 mL of 2.0 M heptane/THF/ethylbenzene solution,1.4 mmol) was added via syringe. The mixture was stirred at −78° C. for1 h, then N-methoxy-N-methylacetamide (0.16 mL, 1.54 mmol) was added.The solution was warmed to rt and was stirred for 4 h. The consumptionof the starting material was monitored by TLC (AcOEt/n-hexane 1:9). Thereaction was quenched by adding sat'd aq ammonium chloride solution (40mL). The layers were separated and the aqueous phase was extracted withether (3×30 mL). The combined organic layers were dried over Na₂SO₄,gravity filtered, and concentrated under reduced pressure. The reactionresidue was purified by silica gel flash chromatography, eluting withAcOEt/n-hexane 2:8, to provide 0.47 g of the title compound as acolorless oil in 86% yield.

Data for 5m (EB-079)

¹H NMR (400 MHz, CDCl₃) 7.53 (d, J=7.2 Hz, 1H), 7.39 (t, J=7.7 Hz, 1H),7.36-7.14 (m, 2H), 6.98 (d, J=15.6 Hz, 1H), 6.11 (dt, J=15.6, 7.6 Hz,1H), 4.33 (q, J=7.1 Hz, 4H), 3.11 (s, 2H), 3.07 (d, J=7.6 Hz, 2H), 2.40(s, 3H), 1.36 (t, J=7.1 Hz, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) 183.9, 169.2 (2C), 134.9, 132.7, 131.3, 129.6,128.7, 126.9, 126.9, 125.9, 87.7, 83.6, 62.1 (2C), 56.8, 36.3, 32.9,23.4, 14.1 (2C) ppm

IR (thin film) 2982, 2936, 2213, 1734, 1679, 1203 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₁H₂₄O₅Cl, 391.1312. found,391.1299.

Diethyl4-acetyl-8-chloro-1H-cyclopenta[b]naphthalene-2,2(3H)-dicarboxylate (6m)

A microwave irradiation vial (10-20 mL) was equipped with a sir bar (1.5cm) and was charged with compound 5m (0.3 g, 0.77 mmol) and1,2-dichlorobenzene (12.8 mL). The reaction was irradiated with stirringat 180° C. for 30 min, turning gold in color. The reaction was directlyadded to a silica gel column, which was eluted with n-hexane to separatethe 1,2-dichlorobenzene and then AcOEt/n-hexane 2:8 to collect the pureproduct. The title compound was isolated as a yellow oil in quant. yield(0.298 g). Small traces of contaminants were observed.

Data for 6m (EB-081)

¹H NMR (400 MHz, CDCl₃) 8.17 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.53 (d,J=7.4 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 4.27-4.17 (m, 4H), 3.76 (s, 2H),3.68 (s, 2H), 2.66 (s, 3H), 1.38-1.13 (m, 6H)

¹³C NMR (100 MHz, CDCl₃) 205.0, 170.9 (2C), 140.5, 136.7, 135.4, 132.3,130.7, 130.0, 126.3, 126.3, 123.7, 121.0, 62.1 (2C), 60.9, 40.1, 39.4,32.3, 14.1 (2C)

IR (thin film) 2981, 2935, 1731, 1697, 1253, 1185 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₁H₂₂O₅Cl, 389.1156. found,389.1166.

Literature Preparation.

The preparation of (E)-(3-(prop-2-yn-1-yloxy)prop-1-en-1-yl)benzene(S16) followed the procedure reported by Lee et al. Org. Lett. 2002, 4,4369.

4-(Cinnamyloxy)-1-phenylbut-2-yn-1-one (5n)

To a flame-dried two-neck 50 mL round-bottomed flask equipped with anargon inlet adapter, a septum, and a stir bar was added PdCl₂(PPh₃)₂(0.024 g, 0.034 mmol), THF (6 mL), triethylamine (0.29 mL, 2.06 mmol),and benzoyl chloride (0.24 mL, 2.06 mmol). The solution was stirred for10 min at rt, and copper(I) iodide (0.013 g, 0.069 mmol) was added allat once through the sidearm turning the reaction from cloudy yellow toclear orange. The reaction was stirred for 10 min, and enyne S16 (0.296g, 1.72 mmol) in THF (0.5 mL) was added all at once via syringe. Thereaction was stirred for 4 h until complete by TLC, in which time thereaction became cloudy and orange. Water was added to the reaction, andthe aqueous layer was separated and extracted with EtOAc (2×). Thecombined organic layers were washed with 1 M hydrochloric acid, sat'd aqammonium chloride, and brine, dried over magnesium sulfate, gravityfiltered, and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography (50 g silica cartridge,0-10% ethyl acetate/hexanes) to yield product 5n as a yellow oil (0.330g, 69%).

Data for 5n (LSK-3-096)

¹H NMR (400 MHz, CDCl₃) 8.16 (d, J=7.5 Hz, 2H), 7.64 (t, J=7.5 Hz, 1H),7.50 (t, J=7.5 Hz, 2H), 7.42 (d, J=7.5 Hz, 2H), 7.34 (t, J=7.5 Hz, 2H),7.27 (t, J=7.5 Hz, 1H), 6.70 (d, J=16.0 Hz, 1H), 6.23 (dt, J=6.2, 16.0Hz, 1H), 4.51 (s, 2H), 4.35 (dd, J=1.2, 6.2 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 177.5, 136.4, 136.3, 143.4, 134.0, 129.7 (2C),128.7 (2C), 128.7 (2C), 128.1, 126.6 (2C), 124.5, 90.3, 84.2, 70.9, 57.1ppm

IR (thin film) 3076, 3059, 3027, 2933, 2850, 2226, 1645, 1596, 1493,1262, 745 cm⁻¹

LRMS (TOF MSMS ES+) m/z (%): 276 (39), 275 (100), 258 (9), 257 (22), 245(8)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₉H₁₇O₂, 277.1229. found 277.1216.

1-(1,3-Dihydronaphtho[2,3-c]furan-4-yl)ethanone (6n) and1-(1,3,9,9a-tetrahydronaphtho[2,3-c]furan-4-yl)ethanone (7n)

To a 2-5 mL microwave irradiation vial equipped with a stir bar wasadded enyne 5n (0.054 g, 0.20 mmol) in DCE (3.3 mL). The reaction wasirradiated with stirring at 180° C. for 30 min to yield a mixture ofproducts 6n, 7n, and other unidentified byproducts, as observed by crude¹H NMR spectroscopy. The crude mixture was purified by silica gel columnchromatography (10 g silica cartridge, 0-15% ethyl acetate/hexanes) toyield 6n (0.015 g, 28%) and 7n (0.008 g, 15%).

Data for 6n (LSK-3-022-001, 28% yield)

¹H NMR (400 MHz, CDCl₃) 7.90 (d, J=8.3 Hz, 1H), 7.82 (d, J=8.3 Hz, 3H),7.68 (d, J=8.3 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 7.51-7.38 (m, 4H), 5.26(s, 2H), 5.01 (s, 2H) ppm

¹³C NMR (125 MHz, CDCl₃) 197.9, 138.0, 137.4, 137.3, 134.0, 133.4,130.5, 129.9 (2C), 129.2, 128.9 (2C), 128.4, 126.7, 126.2, 125.6, 121.572.7, 72.3 ppm

IR (thin film) 3061, 3019, 2921, 2852, 1765, 1662, 1578, 1233, 1055, 751cm⁻¹

LRMS (TOF MSMS ES+) m/z (%): 274 (100), 273 (80), 259 (71), 245 (41),231 (45)

HRMS (TOF MS ES+) [M] calcd for C₁₉H₁₄O₂, 274.0994. found: 274.0957.

Data for 7n (LSK-3-022-002, 15% yield)

¹H NMR (400 MHz, CDCl₃) 7.82 (d, J=7.2 Hz, 2H), 7.56 (d, J=7.2 Hz, 1H),7.44 (t, J=7.6 Hz, 3H), 7.27-7.23 (m, 1H), 7.16 (t, J=7.2 Hz, 1H), 7.06(t, J=7.6 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 4.69 (dd, J=1.6, 16.0 Hz,1H), 4.44 (t, J=8.4 Hz, 1H), 4.32 (dd, J=2.8, 16.0 Hz, 1H), 3.59 (t,J=8.8 Hz, 1H), 3.25-3.17 (m, 1H), 3.00 (dd, J=6.4, 14.8 Hz, 1H), 2.83(t, J=15.2 Hz, 1H) ppm

¹³C NMR (125 MHz, CDCl₃) 196.9, 150.5, 137.0, 133.9, 133.4, 129.9, 129.6(2C), 128.9, 128.7 (2C), 128.2, 127.6, 127.0, 126.0, 74.0, 69.5, 41.1,31.5 ppm

IR (thin film) 3061, 3025, 2921, 2851, 1723, 1663, 1595, 1449, 1230,1042 cm⁻¹

LRMS (TOF MSMS ES+) m/z (%): 277 (5), 276 (100), 275 (40), 261 (25),

HRMS (TOF MS ES+) [M] calcd for C₁₉H₁₆O₂, 276.1150. found, 276.1126.

Literature Preparation.

The preparation of 4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (S17)followed the procedure reported by Gilbertson et al., J. Org. Chem.2007, 72, 799.

N-Cinnamyl-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (S18)

(Sylvester, et al. J. Am. Chem. Soc. 2009, 131, 8772) To a flame-driedtwo-neck 100 mL round-bottomed flask equipped with an argon inletadapter, a septum, and a stir bar was added alkyne S17 (1.30 g, 6.22mmol) and anhydrous potassium carbonate (3.44 g, 24.9 mmol). The flaskwas flushed with argon, and then MeCN (65 mL) was added with stirring.Cinnamyl bromide (1.84 mL, 12.4 mmol) was added dropwise, turning thereaction yellow. The reaction was heated at reflux for 18 h, and thencooled to rt. The MeCN was then removed by concentration under reducedpressure. The residue was taken up in sat'd aq sodium bicarbonate andextracted with Et₂O (3×). The combined organic layers were washed withbrine, dried over magnesium sulfate, gravity filtered, and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography (50 g silica cartridge, 0-20% ethylacetate/hexanes) to yield the enyne S18 as a light yellow solid (1.90 g,94%), previously characterized (Gibson, et al. Chem. Eur. J. 2007, 13,709).

N-Cinnamyl-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (5o)

Follows general procedure A: enyne S18 (1.25 g, 3.84 mmol), THF (10 mL),n-butyllithium (2.2 mL of a 1.6 M solution in hexanes, 2.55 mmol),N,N-dimethylacetamide (0.27 mL, 2.96 mmol), THF (10 mL), borontrifluoride diethyl etherate (0.46 mL, 3.69 mmol), and acetic acid (0.21mL, 3.69 mmol). The reaction turned purple and then golden after theaddition of n-butyllithium, and orange after the addition of aceticacid. The reaction was complete after 3 h. The crude product waspurified by silica gel column chromatography (100 g silica cartridge,0-30% ethyl acetate/hexanes) to yield the product 5o as a white solid(0.485 g, 45% yield).

Data for 5o (LSK-3-017)

¹H NMR (400 MHz, CDCl₃) 7.78 (d, J=7.9 Hz, 2H), 7.38-7.28 (m, 7H), 6.57(d, J=15.8 Hz, 1H), 6.09 (dt, J=6.9, 15.8 Hz, 1H), 4.28 (s, 2H), 4.00(d, J=6.9 Hz, 2H), 2.44 (s, 3H), 2.11 (s, 3H) ppm

¹³C NMR (100 MHz, CDCl₃) 183.3, 144.1, 135.9, 135.6, 135.4, 129.8 (2C),128.7 (2C), 128.3, 127.8 (2C), 126.6 (2C), 122.5, 84.8, 84.3, 49.3,36.1, 32.4, 21.6 ppm

IR (thin film) 3060, 3028, 2921, 2859, 2255, 2209, 1679, 1597, 1494,1349, 1222, 1162, 755, 736 cm⁻¹

LRMS (TOF MS ES+) m/z (%): 367 (7), 366 (20), 365 (31), 364 (100), 352(12), 198 (15), 195 (63), 155 (25)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₁H₂₂NO₃S, 368.1276. found:368.1309.

1-(2-Tosyl-2,3-dihydro-1H-benzo[f]isoindol-4-yl)ethanone (6o) and1-(2-Tosyl-2,3,9,9a-tetrahydro-1H-benzo[f]isoindol-4-yl)ethanone (7o)

To a 2-5 mL microwave irradiation vial equipped with a stir bar wasadded enyne 5o (0.051 g, 0.14 mmol) in DCE (2.3 mL). The reaction wasirradiated with stirring at 180° C. for 10 min to yield the products 6oand 7o (0.044 g, 86%). Based on ¹H NMR analysis the ratio of 6o to 7owas 1:1.8. Naphthalene 6o was not separable from dihydronaphthalene 7oby column chromatography, but enough of each product was separated byHPLC (15% ethyl acetate/hexanes) for characterization.

Data for 6o (LSK-3-022-001, 30% yield by ¹H NMR)

¹H NMR (400 MHz, CDCl₃) 7.86-7.80 (m, 4H), 7.71 (s, 1H), 7.55-7.48 (m,2H), 7.33 (d, J=8.2 Hz, 2H), 4.74 (s, 2H), 4.71 (s, 2H), 2.67 (s, 3H),2.40 (s, 3H) ppm

¹³C NMR (100 MHz, CDCl₃) 203.9, 144.0, 134.8, 133.6, 133.4, 133.1,132.9, 129.9 (2C), 128.9, 128.6, 127.8 (2C), 127.2, 126.5, 124.6, 123.7,52.8, 52.8, 32.0, 21.5 ppm

IR (thin film) 3060, 2949, 2919, 2851, 1680, 1625, 1593, 1491, 1346,1160, 1094, 816, 767 cm⁻¹

LRMS (TOF MS ES+) m/z (%): 366 (33), 196 (8), 197 (100)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂H₂₀NO₃S, 366.1164. found: 366.1147.

Data for 7o (LSK-3-022-002, 56% yield by ¹H NMR)

¹H NMR (400 MHz, CDCl₃) 7.76 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H),7.24-7.17 (m, 3H), 7.10 (d, J=6.9 Hz, 1H), 4.54 (dd, J=1.7, 17.9 Hz,1H), 3.96 (t, J=8.9 Hz, 1H), 3.91 (dd, J=2.5, 17.9 Hz, 1H), 2.97 (m,1H), 2.87 (t, J=9.6 Hz, 1H), 2.83 (dd, J=6.2, 14.8 Hz, 1H), 2.52 (t,J=14.8 Hz, 1H), 2.44 (s, 3H), 2.34 (s, 3H) ppm

¹³C NMR (100 MHz, CDCl₃) 200.8, 147.9, 143.9, 134.5, 132.9, 132.0 (2C),129.9 (2C), 128.1, 127.9, 127.8 (2C), 127.1, 125.6, 52.9, 51.7, 40.1,32.3, 30.0, 21.6 ppm

IR (thin film) 3056, 2945, 2916, 2851, 1680, 1593, 1499, 1344, 1160,1094, 817, 751 cm⁻¹

LRMS (TOF MS ES+)m/z (%): 368 (100), 197 (92), 194 (8), 185 (12), 184(8)

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₁H₂₂NO₃S, 368.1320. found,368.1349.

N-(3-(2-Chlorophenyl)allyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (S19)

To an oven-dried, 100 mL three-necked round-bottomed flask equipped witha stir bar, two septa and a nitrogen inlet adaptor was added4-methyl-N-(prop-2-yn-1-yl) benzenesulfonamide (S17) (1.0 g, 4.8 mmol)and potassium carbonate (2.69 g, 19.2 mmol). The flask was evacuated andrefilled with nitrogen three times, then MeCN (60 mL) was added.(E)-1-(3-Bromoprop-1-en-1-yl)-2-chlorobenzene (S14) (1.66 g, 7.2 mmol)was added dropwise via syringe, turning the solution dark yellow. Themixture was heated at reflux and stirred overnight. The consumption ofthe starting material was monitored by TLC (AcOEt/n-hexane 1:9). Thesolvent was removed in vacuo, and the reaction residue was taken up insat'd NaHCO₃ solution (70 mL) and extracted with ether (3×50 mL). Thecombined organic layers were washed with brine (70 mL), dried overNa₂SO₄, gravity filtered, and concentrated under reduced pressure. Thereaction residue was purified by silica gel flash chromatography,eluting with AcOEt/n-hexane 1:9, to provide 1.35 g of the title compoundas a light yellow solid in a 78% yield.

N-(3-(2-Chlorophenyl)allyl)-4-methyl-N-(4-oxopent-2-yn-1-yl)benzenesulfonamide (5p)

An oven-dried, 100 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with compound S19 (1.0 g, 2.8 mmol) and THF (40mL). The solution was cooled to −78° C. in a dry ice/acetone bath for 15min, then n-BuLi (1.74 mL of a 1.6 M n-hexane solution, 2.8 mmol) wasadded via syringe. The mixture was stirred at −78° C. for 1 h, thenN,N-dimethylacetamide (0.19 mL, 2.1 mmol) and BF₃.Et₂O (0.26 mL, 2.1mmol) were added. The solution was stirred at −78° C. for an additional3 h. The consumption of the starting material was monitored by TLC(AcOEt/n-hexane 3:7). The reaction was quenched by adding sat'd aqammonium chloride solution (50 mL). The layers were separated and theaqueous phase was extracted with ether (3×30 mL). The combined organiclayers were dried over Na₂SO₄, gravity filtered, and concentrated underreduced pressure. The reaction residue was purified by silica gel flashchromatography, eluting with AcOEt/n-hexane 2:8, to provide 0.48 g ofthe title compound as a light yellow solid in a 43% yield.

¹H NMR (400 MHz, CDCl₃) 7.76 (d, J=8.2 Hz, 2H), 7.53-7.40 (m, 1H),7.35-7.31 (m, 3H), 7.28-7.10 (m, 2H), 6.96 (d, J=15.7 Hz, 1H), 6.07 (dt,J=15.7, 6.8 Hz, 1H), 4.28 (s, 2H), 4.02 (d, J=6.7 Hz, 2H), 2.43 (s, 3H),2.11 (s, 3H) ppm

¹³C NMR (100 MHz, CDCl₃) 183.2, 144.3, 135.5, 134.2, 133.2, 131.6, 129.9(2C), 129.8, 129.4, 127.9 (2C), 127.2, 127.1, 125.6, 84.9, 84.2, 49.5,36.4, 32.5, 21.6 ppm

IR (thin film) 2920, 2209, 1679, 1351, 1162 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₁H₂₁NO₃SCl: 402.0931. found,402.0951.

1-(8-Chloro-2-tosyl-2,3-dihydro-1H-benzo[f]isoindol-4-yl)ethanone (6p)and1-(8-chloro-2-tosyl-2,3,9,9a-tetrahydro-1H-benzo[f]isoindol-4-yl)ethanone(7p)

A microwave irradiation vial (2-5 mL) was equipped with a sir bar (1 cm)and was charged with compound 5p (0.07 g, 0.17 mmol) and1,2-dichlorobenzene (3 mL). The reaction was irradiated with stirring at180° C. for 10 min, turning brown in color. The reaction was directlyadded to a silica gel column, which was eluted with n-hexane to separatethe 1,2-dichlorobenzene, and then AcOEt/n-hexane 2:8 to collect the pureproducts. The title compounds 6p and 7p were isolated as a 1:2 mixtureof inseparable products in a 71% yield (0.048 g).

Data for 6p, 7p (EB-067)

¹H NMR (400 MHz, CDCl₃) 8.18 (s, 1H minor) 7.80-7.71 (m, 3H major and 3Hminor), 7.59 (d, J=7.4 Hz, 1H minor), 7.47-7.23 (m, 3H major and 2Hminor), 7.16 (t, J=7.8 Hz, 1H major), 7.00 (d, J=7.6 Hz, 1H major), 4.77(s, 2H minor), 4.70 (s, 2H minor), 4.55 (d, J=18.0 Hz, 1H major), 4.10(m, 1H major), 3.99 (t, J=8.1 Hz, 1H major), 3.90 (d, J=18.0 Hz, 1Hmajor), 3.38 (dd, J=15.4, 6.1 Hz, 1H major), 3.04-2.79 (m, 2H major),2.65 (s, 3H minor), 2.43 (s, 3H major), 2.39 (s, 3H minor), 2.31 (s, 3Hmajor) ppm

¹³C NMR (100 MHz, CDCl₃) 203.6 (minor), 200.3 (major), 148.6 (major),144.2 (minor), 144.1 (major), 136.4 (minor), 134.2 (minor), 134.0(major), 133.6 (1C major and 1C minor), 133.1 (minor), 132.9 (1C minorand 1C major), 132.7 (major), 132.5 (minor), 130.9 (minor), 130.2(minor), 130.1 (2C minor), 130.0 (2C major), 129.1 (2C major), 127.9(major), 127.8 (2C minor), 127.8 (major), 127.0 (minor), 126.9 (minor),124.2 (major), 123.8 (minor), 120.2 (minor), 53.1 (minor), 52.8 (minor),51.7 (major), 39.6 (major), 32.1 (minor), 30.1 (major), 28.6 (major),21.7 (minor), 21.6 (major), 14.3 (major).

1-(8-Chloro-2-tosyl-2,3-dihydro-1H-benzo[f]isoindol-4-yl)ethanone (6p)

A microwave irradiation vial (10-20 mL) was equipped with a sir bar andwas charged with compound 5p (0.3 g, 0.75 mmol) and 1,2-dichlorobenzene(12.4 mL). The reaction was irradiated with stirring at 180° C. for 3 h,turning black in color. The solution was directly added to a silica gelcolumn, which was eluted with n-hexane to separate the1,2-dichlorobenzene, and then AcOEt/n-hexane 2:8 to collect the pureproduct. The title compound was isolated as a brown solid in a 31% yield(0.093 g).

¹H NMR (400 MHz, CDCl₃) 8.13 (s, 1H), 7.78 (d, J=8.2 Hz, 2H), 7.70 (d,J=8.5 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.32 (d,J=8.0 Hz, 2H), 4.73 (s, 2H), 4.69 (s, 2H), 2.63 (s, 3H), 2.38 (s, 3H).

¹³C NMR (100 MHz, CDCl₃) 203.6, 144.2, 136.3, 134.1, 133.5, 133.1,132.6, 130.9, 130.2, 130.0 (2C), 127.8 (2C), 127.0, 126.9, 123.8, 120.2,53.1, 52.8, 32.1, 21.6.

IR (thin film) 2921, 1691, 1346, 1160 cm⁻¹

HRMS (TOF MS ES+) [M−H]⁺ calcd for C₂₁H₁₇NO₃SCl: 398.0618. found,398.0609.

General Procedure for the Buchwald-Hartwig Couplings

An oven-dried sealed tube (0.5-2 mL) was equipped with a sir bar andcharged with the precatalyst (0.004 mmol). The tube was closed with aseptum, then evacuated and refilled with nitrogen three times through aneedle. LHMDS (1M solution in THF, 0.32 mmol) and compound LSK-3-97(0.16 mmol) in dry THF (0.3 mL) were added. Finally the amine (0.24mmol) in dry THF (0.3 mL) was added at room temperature. The resultingsolution was heated at 85° C. in an oil bath and stirred for 3 hours.The consumption of the starting material was monitored by TLC. At theend of the reaction, the mixture was cooled to room temperature, dilutedwith saturated aqueous ammonium chloride solution (10 mL), and thenextracted with AcOEt (3×12 mL). The combined organic layers were driedover Na₂SO₄, gravity filtered and concentrated in vacuo. The crudeproduct was finally purified by flash chromatography over silica gel.

1-(6-(Dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(8)

An oven-dried sealed tube (0.5-2 mL) was equipped with a stir bar andcharged with the precatalyst (0.003 g, 0.004 mmol). The tube was closedwith a septum, then evacuated and refilled with nitrogen three timesthrough a needle. LHMDS (0.3 mL of a 1.0 M solution in THF, 0.32 mmol)and compound 6b (0.038 g, 0.16 mmol) in THF (0.3 mL) were added viasyringe. Finally, dimethylamine (0.3 mL of a 2.0 M solution in THF, 0.24mmol) in THF (0.3 mL) was added at rt via syringe. The resultingsolution was heated at 85° C. in an oil bath and stirred for 3 h. Theconsumption of the starting material was monitored by TLC. Once thereaction was complete, the mixture was cooled rt, diluted with sat'd aqammonium chloride solution (10 mL), and then extracted with AcOEt (3×12mL). The combined organic layers were dried over Na₂SO₄, gravityfiltered, and concentrated in vacuo. The crude product was purified byflash chromatography (n-hexane/AcOEt 9.25:0.7) and the pure product wasisolated as a yellow solid (70% yield).

¹H NMR (400 MHz, CDCl₃) 7.64 (d, J=9.0 Hz, 1H), 7.56 (s, 1H), 7.11 (dd,J=9.1, 2.5 Hz, 1H), 6.87 (d, J=2.5 Hz, 1H), 3.16-2.87 (m, 10H), 2.65 (s,3H), 2.12 (p, J=7.3 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 207.0, 148.8, 140.5, 138.9, 133.0, 130.1,128.9, 126.6, 124.1, 115.8, 103.5, 40.9 (2C), 32.5, 32.2, 32.0, 26.2 ppm

IR (thin film) 2952, 2917, 2849, 2359, 2339, 1685, 1620, 1510, 1344 cm⁻¹

HRMS (TOF MS ES+) [M] calcd for C₁₇H₂₀NO: 254.1545. found, 254.1536.

Synthesis of1-(6-(pyrrolidin-1-yl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanoneEB-013

Substrate EB-013 was synthesized following the general procedure for theBuchwald-Hartwig couplings: precatalyst (0.003 g, 0.004 mmol), LHMDS(0.3 mL of a 1M solution in THF, 0.32 mmol), LSK-3-97 (0.038 g, 0.16mmol), pyrrolidine (0.017 g, 0.02 mL, 0.24 mmol) dry THF (0.3 mL). Thetitle compound was isolated (n-hexane/AcOEt 9:1, 59% yield) as a yellowsolid.

¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J=9.0 Hz, 1H), 7.54 (s, 1H), 6.94(dd, J=8.9, 2.6 Hz, 1H), 6.69 (s, 1H), 3.48-3.20 (m, 4H), 2.99 (q, J=6.8Hz, 4H), 2.65 (s, 3H), 2.24-1.87 (m, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 207.1, 146.1, 140.6, 138.0, 132.6, 130.4,129.1, 126.1, 124.3, 115.1, 101.9, 47.9, 32.5, 32.2, 31.9, 29.8, 26.2,25.6 (2CH₂) ppm

IR (thin film) 2957, 2919, 2841, 1680, 1618, 1509, 1353 cm⁻¹

HRMS TOF MS ES+: C₁₉H₂₂NO Calculated: 280.1701. Found: 280.1713.

Synthesis of1-(6-morpholino-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(EB-014)

Substrate EB-014 was synthesized following the general procedure for theBuchwald-Hartwig couplings: precatalyst (0.003 g, 0.004 mmol), LHMDS(0.3 mL of a 1M solution in THF, 0.32 mmol), LSK-3-97 (0.038 g, 0.16mmol), morpholine (0.021 g, 0.02 mL, 0.24 mmol) dry THF (0.3 mL). Thetitle compound was isolated (n-hexane/AcOEt 8:2, 58% yield) as a yellowsolid.

¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, J=9.0 Hz, 1H), 7.60 (s, 1H),7.22-7.14 (m, 1H), 7.10 (s, 1H), 3.90 (t, J=4.7 Hz, 4H), 3.36-3.13 (m,4H), 3.02 (td, J=8.7, 8.0, 5.9 Hz, 4H), 2.64 (s, 3H), 2.14 (p, J=7.3 Hz,2H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.7, 146.1, 140.7, 138.0, 133.6, 129.6,129.0, 128.4, 124.2, 118.2, 107.2, 67.0 (2CH₂), 49.8, 32.5, 32.3, 32.2,26.3 (2CH₂) ppm

IR (thin film) 2956, 2919, 2850, 1689, 1618, 1227, 1121 cm⁻¹

HRMS TOF MS ES+: C₁₉H₂₂NO₂ Calculated: 296.1651. Found: 296.1636.

Synthesis of1-(6-(benzylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(EB-016)

Substrate EB-016 was synthesized following the general procedure for theBuchwald-Hartwig couplings: precatalyst (0.003 g, 0.004 mmol), LHMDS(0.3 mL of a 1M solution in THF, 0.32 mmol), LSK-3-97 (0.038 g, 0.16mmol), phenylmethanamine (0.026 g, 0.026 mL, 0.24 mmol) dry THF (0.3mL). The title compound was isolated (n-hexane/AcOEt 8.5:1.5, 89% yield)as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.67-7.46 (m, 2H), 7.45-7.31 (m, 4H),7.31-7.16 (m, 1H), 6.87 (dd, J=8.8, 2.4 Hz, 1H), 6.75 (d, J=2.3 Hz, 1H),4.40 (s, 3H), 2.98 (t, J=7.3 Hz, 4H), 2.47 (s, 3H), 2.11 (p, J=7.3 Hz,2H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.9, 145.8, 140.6, 139.1, 139.0, 132.9,130.2, 129.2, 128.8 (2CH), 127.7 (2CH), 127.4, 127.3, 124.3, 117.1,102.4, 48.4, 32.4, 32.2, 31.9, 26.2 ppm

IR (thin film) 3408, 3027, 2951, 2841, 1684, 1626, 1522, 1256 cm⁻¹

HRMS TOF MS ES+: C₂₂H₂₂NO Calculated: 316.1701. Found: 316.1690.

Synthesis of1-(6-(piperidin-1-yl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(EB-019)

Substrate EB-019 was synthesized following the general procedure for theBuchwald-Hartwig couplings: precatalyst (0.003 g, 0.004 mmol), LHMDS(0.3 mL of a 1M solution in THF, 0.32 mmol), LSK-3-97 (0.038 g, 0.16mmol), piperidine (0.02 g, 0.024 mL, 0.24 mmol) dry THF (0.3 mL). Thetitle compound was isolated (n-hexane/AcOEt 9:1, 45% yield) as a yellowoil.

¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J=9.0 Hz, 1H), 7.57 (s, 1H),7.32-7.17 (m, 1H), 7.08 (s, 1H), 3.32-3.11 (m, 4H), 3.01 (td, J=7.2, 3.1Hz, 4H), 2.64 (s, 3H), 2.13 (p, J=7.3 Hz, 2H), 1.87-1.67 (m, 4H),1.69-1.51 (m, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.9, 150.6, 140.3, 140.1, 133.5, 129.8,128.7, 128.0, 124.0, 119.5, 107.4, 51.0 (2CH₂), 32.4, 32.3, 32.2, 26.3,26.0 (2CH₂), 24.4 ppm

IR (thin film) 2932, 2851, 2803, 1690, 1613, 1503, 1234 cm⁻¹

HRMS TOF MS ES+: C₂₀H₂₄NO Calculated: 294.1858. Found: 294.1871.

Synthesis of1-(6-((4-methoxyphenyl)amino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(EB-020)

Substrate EB-020 was synthesized following the general procedure for theBuchwald-Hartwig couplings: precatalyst (0.003 g, 0.004 mmol), LHMDS(0.3 mL of a 1M solution in THF, 0.32 mmol), LSK-3-97 (0.038 g, 0.16mmol), 4-methoxyaniline (0.029 g, 0.24 mmol), dry THF (0.6 mL). Thetitle compound was isolated (n-hexane/AcOEt 8:2, 71% yield) as a brownsolid.

¹H NMR (400 MHz, CDCl₃) δ 7.69-7.52 (m, 2H), 7.18 (s, 1H), 7.15-7.03 (m,3H), 6.88 (d, J=8.8 Hz, 2H), 5.75 (s, 1H), 3.81 (s, 3H), 3.01 (dd,J=9.6, 4.9 Hz, 4H), 2.58 (s, 3H), 2.12 (p, J=7.3 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.5, 155.6, 143.1, 140.9, 139.9, 135.5,133.0, 130.0, 129.3, 128.3, 124.36 (2CH), 122.3, 118.0, 114.8 (2CH),106.5, 55.7, 32.5, 32.3, 32.1, 26.2 ppm

IR (thin film) 3369, 2953, 2836, 1683, 1624, 1508, 1241 cm⁻¹

HRMS TOF MS ES+: C₂₂H₂₂NO₂ Calculated: 332.1651. Found: 332.1648.

Synthesis of1-(6-(phenylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(EB-030)

Substrate EB-030 was synthesized following the general procedure for theBuchwald-Hartwig couplings: precatalyst (0.02 g, 0.003 mmol), LHMDS(0.22 mL of a 1M solution in THF, 0.22 mmol), LSK-3-97 (0.027 g, 0.11mmol), aniline (0.015 g, 0.015 mL, 0.16 mmol) dry THF (0.3 mL). Thetitle compound was isolated (n-hexane/AcOEt 8:2, 78% yield) as a yellowsolid.

¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J=8.8 Hz, 1H), 7.62 (s, 1H), 7.36 (s,1H), 7.33-7.19 (m, 3H), 7.12 (d, J=7.7 Hz, 2H), 6.96 (t, J=7.3 Hz, 1H),5.89 (s, 1H), 3.03 (t, J=7.1 Hz, 4H), 2.61 (s, 3H), 2.14 (p, J=7.3 Hz,2H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.3, 142.9, 141.2, 140.9, 140.7, 133.3,129.8, 129.5 (2CH), 129.3, 128.9, 124.3, 121.50, 119.3, 118.1 (2CH),109.3, 32.5, 32.3, 32.2, 26.2 ppm

IR (thin film) 3361, 2953, 1680, 1624, 1596, 1497, 1397 cm⁻¹

HRMS TOF MS ES+: C₂₁H₁₉NO Calculated: 301.1467. Found: 301.1468.

Literature Preparation.

5-Hexynal was prepared from 5-hexyn-1-ol through an oxidation reactionwith PCC, which was reported by Kobayashi et al. Chem. Asian J. 2007, 2,135-144. Diethyl 3-chlorobenzylphosphonate was prepared from1-(bromomethyl)-3-chlorobenzene and triethyl phosphite via the procedurereported by Luscombe et al. Macromolecules 2011, 44, 512-520.

Synthesis of 1-chloro-3-(hept-1-en-6-yn-1-yl)benzene (EB-024)

An oven-dried 250 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with 3-chlorobenzylphosphonate (4.74 g, 18 mmol)and dry THF (60 mL). The solution was cooled to 0° C. in an ice bath for15 min, then n-BuLi (12 mL of a 1.6 M n-hexane solution, 19 mmol) wasadded dropwise over 10 min, via syringe. The mixture was stirred at 0°C. for 30 min, then 5-hexynal (1.0 g, 10 mmol) in dry THF (40 mL) wasadded. The solution was warmed to room temperature and was stirred for 3h. The consumption of the starting material was monitored by TLC(AcOEt/n-hexane 1:9). The reaction was quenched by adding saturatedaqueous ammonium chloride solution (70 mL). The layers were separatedand the aqueous phase was extracted with ether (3×50 mL). The combinedorganic layers were washed with brine (2×50 mL), dried over Na₂SO₄,gravity filtered and concentrated under reduced pressure. The reactionresidue was purified by silica gel flash chromatography, eluting withAcOEt/n-hexane 0.5:9.5, to provide 1.9 g of the title compound as acolorless oil in a 93% yield.

Synthesis of 9-(3-chlorophenyl)non-8-en-3-yn-2-one (EB-026)

An oven-dried 100 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with compound EB-024 (0.7 g, 3.4 mmol) and dryTHF (40 mL). The solution was cooled to −78° C. in a dry ice/acetonebath for 15 min, then LDA (2 mL of a 2 M heptane/THF/ethylbenzenesolution, 4.0 mmol) was added via syringe. The mixture was stirred at−78° C. for 1 h, then N-methoxy-N-methylacetamide (0.39 g, 0.4 mL, 3.7mmol) was added. The solution was warmed to room temperature and wasstirred for 4 h. The consumption of the starting material was monitoredby TLC (AcOEt/n-hexane 2:8). The reaction was quenched by addingsaturated aqueous ammonium chloride solution (70 mL). The layers wereseparated and the aqueous phase was extracted with ether (3×50 mL). Thecombined organic layers were dried over Na₂SO₄, gravity filtered andconcentrated under reduced pressure. The reaction residue was purifiedby silica gel flash chromatography, eluting with AcOEt/n-hexane 1.5:8.5,to provide 0.52 g of the title compound as a colorless oil in a 60%yield.

¹H NMR (400 MHz, CDCl₃) δ 7.33 (s, 1H), 7.19 (td, J=7.6, 7.2, 2.2 Hz,3H), 6.37 (d, J=15.8 Hz, 1H), 6.31-6.04 (m, 1H), 2.42 (t, J=7.1 Hz, 2H),2.34 (d, J=8.9 Hz, 5H), 1.76 (p, J=7.2 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 184.9, 139.4, 134.6, 130.7, 130.0, 129.9,127.2, 126.0, 124.4, 93.4, 81.9, 32.9, 32.0, 27.3, 18.5 ppm

IR (thin film) 2934, 2210, 1674, 1229, 964 cm⁻¹

HRMS TOF MS ES+: C₁₅H₁₆ClO Calculated: 247.0890. Found: 247.0886.

Synthesis of1-(5-chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(EB-028-A) and1-(7-chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(EB-028-B)

A microwave irradiation vial was equipped with a sir bar and was chargedwith compound EB-026 (0.2 g, 0.81 mmol) and 1,2-dichlorobenzene (13.5mL). The reaction was irradiated with stirring at 180° C. for 3 h,turning gold in color. The solution was directly charged into a silicagel column, which was eluted with n-hexane separate the1,2-dichlorobenzene and then AcOEt/n-hexane 1:9 to collect the pureproducts. The title compounds were isolated as a 1.4:1 mixture ofunseparable isomers in a 79% yield.

¹H NMR (400 MHz, CDCl₃) δ 7.73-7.58 (m, 2H major isomer and 2H minorisomer), 7.53 (s, 1H major isomer), 7.44 (d, J=7.4 Hz, 1H minor isomer),7.35-7.21 (m, 1H major isomer and 1H minor isomer), 3.02-2.97 (m, 4Hmajor isomer and 4H minor isomer), 2.60 (s, 3H, minor isomer), 2.59 (s,3H, major isomer), 2.14-2.06 (m, 2H major isomer and 2H minor isomer)ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.7 (minor isomer), 205.5 (major isomer),144.6 (major isomer), 144.0 (major isomer), 141.3 (minor isomer), 140.3(major isomer), 135.1 (major isomer), 134.7 (minor isomer), 134.6 (1Cmajor isomer and 1C minor isomer), 133.9 (major isomer), 131.2 (majorisomer), 129.4 (minor isomer), 127.7 (minor isomer), 127.5 (majorisomer), 126.7 (major isomer), 126.7 (minor isomer), 126.3 (minorisomer), 126.0 (major isomer), 125.4 (minor isomer), 124.0 (minorisomer), 123.4 (major isomer), 33.7 (minor isomer), 32.4 (minor isomer),32.4 (major isomer), 32.2 (major isomer), 32.1 (major isomer), 31.6(minor isomer), 26.1 (major isomer), 25.8 (minor isomer) ppm

IR (thin film) 2949, 1969, 1598, 1418, 1142 cm⁻¹

HRMS TOF MS ES+: C₁₅H₁₄ClO Calculated: 245.0733. Found: 245.0728.

Synthesis of1-(7-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(EB-041-A) and 1-(2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(EB-041-B)

Substrates EB-041-A and EB-041-B were synthesized from EB-028-A andEB-028-B respectively, following the general procedure for theBuchwald-Hartwig couplings. Compound EB-041-A was isolated(n-hexane/AcOEt 9.5:0.5, 52% yield) as a yellow oil. Compound EB-041-Bwas isolated as colorless oil in a 39% yield and was previouslycharacterized (2.21a/LSK-3-046).

¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J=9.3 Hz, 1H), 7.54 (s, 1H), 7.11(dd, J=9.3, 2.5 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 3.03 (s, 6H), 3.02-2.95(m, 4H), 2.63 (s, 3H), 2.12 (p, J=7.3 Hz, 2H).

¹³C NMR (100 MHz, CDCl₃) δ 206.6, 148.3, 143.5, 136.0, 134.9, 134.5,125.3, 122.9, 121.7, 116.4, 106.9, 40.9 (2CH₃), 32.6, 32.3, 32.1, 26.3.

IR (thin film) 2949, 2842, 2799, 1687, 1624, 1612, 1509, 1356, 1208,1143 cm⁻¹

HRMS TOF MS ES+: C₁₇H₁₉NO Calculated: 253.1467. Found: 253.1471.

Literature Preparation.

5-Hexynal was prepared from 5-hexyn-1-ol through an oxidation reactionwith PCC, which was reported by Kobayashi.¹ Diethyl2-chlorobenzylphosphonate was prepared from1-(bromomethyl)-2-chlorobenzene and triethyl phosphite via the procedurereported by Luscombe.

Synthesis of 1-chloro-2-(hept-1-en-6-yn-1-yl)benzene (EB-035)

An oven-dried 250 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with 3-chlorobenzylphosphonate (3.9 g, 15 mmol)and dry THF (60 mL). The solution was cooled to 0° C. in an ice bath for15 min, then n-BuLi (12 mL of a 1.6 M n-hexane solution, 19 mmol) wasadded dropwise over 10 min, via syringe. The mixture was stirred at 0°C. for 30 min, then 5-hexynal (1.0 g, 10 mmol) in dry THF (40 mL) wasadded. The solution was warmed to room temperature and was stirred for 3h. The consumption of the starting material was monitored by TLC(AcOEt/n-hexane 0.5:9.5). The reaction was quenched by adding saturatedaqueous ammonium chloride solution (70 mL). The layers were separatedand the aqueous phase was extracted with ether (3×50 mL). The combinedorganic layers were washed with brine (2×50 mL), dried over Na₂SO₄,gravity filtered and concentrated under reduced pressure. The reactionresidue was purified by silica gel flash chromatography, eluting withAcOEt/n-hexane 0.5:9.5, to provide 1.11 g of the title compound as acolorless oil in 54% yield.

Synthesis of 9-(2-chlorophenyl)non-8-en-3-yn-2-one (EB-037)

An oven-dried 100 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with compound EB-035 (1.11 g, 5.4 mmol) and dryTHF (25 mL). The solution was cooled to −78° C. in a dry ice/acetonebath for 15 min, then n-BuLi (3.37 mL of a 1.6 M n-hexane solution, 5.4mmol) was added via syringe. The mixture was stirred at −78° C. for 40min, then N,N-dimethylacetamide (0.52 g, 0.55 mL, 5.9 mmol) and BF₃.Et₂O(0.84 g, 0.74 mL, 5.9 mmol) were added. The solution was stirred at −78°C. for an additional 3 h. The consumption of the starting material wasmonitored by TLC (AcOEt/n-hexane 0.2:9.8). The reaction was quenched byadding saturated aqueous ammonium chloride solution (35 mL). The layerswere separated and the aqueous phase was extracted with ether (3×30 mL).The combined organic layers were dried over Na₂SO₄, gravity filtered andconcentrated under reduced pressure. The reaction residue was purifiedby silica gel flash chromatography, eluting with AcOEt/n-hexane 0.2:9.8to 1:9, to provide 0.67 g of the title compound as a yellow oil in a 50%yield.

¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J=7.6 Hz, 1H), 7.33 (d, J=7.8 Hz,1H), 7.24-7.10 (m, 2H), 6.80 (d, J=15.7 Hz, 1H), 6.16 (dt, J=15.7, 7.0Hz, 1H), 2.43 (t, J=7.1 Hz, 2H), 2.37 (t, J=7.1 Hz, 2H), 2.33 (s, 3H),1.79 (p, J=7.1 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 184.9, 135.6, 132.7, 132.0, 129.7, 128.3,127.6, 126.9, 126.8, 93.5, 81.9, 32.9, 32.2, 27.2, 18.5 ppm

IR (thin film) 3061, 2933, 2862, 2210, 1647, 1437, 1230 cm⁻¹

HRMS TOF MS ES+: C₁₅H₁₆ClO Calculated: 247.0890. Found: 247.0874.

Synthesis of1-(8-chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(EB-038)

A microwave irradiation vial (10-20 mL) was equipped with a sir bar (1.5cm) and was charged with compound EB-037 (0.2 g, 0.81 mmol) and1,2-dichlorobenzene (13.5 mL). The reaction was irradiated with stirringat 180° C. for 3 h, turning gold in color. The solution was directlycharged into a silica gel column, which was eluted with n-hexane toseparate the 1,2-dichlorobenzene and then AcOEt/n-hexane 1:9 to collectthe pure product. The title compound was isolated as a yellow solid in a86% yield (0.17 g).

¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.53 (d,J=7.3 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 3.12 (t, J=7.3 Hz, 2H), 3.05 (t,J=7.3 Hz, 2H), 2.64 (s, 3H), 2.19 (p, J=7.3 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.0, 144.9, 140.5, 135.2, 132.2, 130.4,129.7, 125.9, 125.8, 123.6, 120.6, 32.8, 32.3, 32.1, 26.2 ppm

IR (thin film) 2952, 1690, 1410, 1350, 1187 cm⁻¹

HRMS TOF MS ES+: C₁₅H₁₄ClO Calculated: 245.0733. Found: 245.0719.

Synthesis of1-(8-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(EB-039)

Substrate EB-039 was synthesized following the general procedure for theBuchwald-Hartwig couplings: precatalyst (0.003 g, 0.04 mmol), LHMDS(0.32 mL of a 1M solution in THF, 0.32 mmol), EB-038 (0.04 g, 0.16mmol), dimethylamine (0.12 mL of a 2M solution in THF, 0.24 mmol) dryTHF (0.3 mL). The title compound was isolated (n-hexane/AcOEt 9.5:0.5,49% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.35 (t,J=7.9 Hz, 1H), 7.06 (d, J=7.3 Hz, 1H), 3.09 (t, J=7.3 Hz, 2H), 3.03 (t,J=7.3 Hz, 2H), 2.87 (s, 6H), 2.64 (s, 3H), 2.16 (p, J=7.3 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.9, 151.1, 142.7, 139.3, 135.4, 129.8,128.6, 125.9, 120.3, 119.5, 114.0, 45.5 (2CH₃), 32.8, 32.4, 32.0, 26.2ppm

IR (thin film) 2940, 2828, 2783, 1695, 1577, 1454, 1192 cm⁻¹

HRMS TOF MS ES+: C₁₇H₂₀NO Calculated: 254.1545. Found: 254.1543.

Literature Preparation.

Diethyl 2-(prop-2-yn-1-yl)malonate was prepared from triethylmethanetricarboxylate through a procedure, which was previously reportedby Brummond et al. J. Am. Chem. Soc. 2002, 124, 15186.(E)-1-(3-bromoprop-1-en-1-yl)-2-chlorobenzene was prepared starting from2-chlorobenzaldehyde via the procedure reported by Fering a et al. Adv.Synth. Catal. 2004, 346, 413.

Synthesis of diethyl2-(3-(2-chlorophenyl)allyl)-2-(prop-2-yn-1-yl)malonate (EB-075)

An oven-dried, 100 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with compound diethyl 2-(prop-2-yn-1-yl)malonate(1.8 g, 9.1 mmol) (E)-1-(3-bromoprop-1-en-1-yl)-2-chlorobenzene (2.1 g,11.0 mmol) and dry THF (60 mL). The solution was cooled to 0° C. in anice bath for 15 min, then NaH (60% in mineral oil, 0.43 g 11.0 mmol) wasadded in one portion. The solution was stirred at 0° C. for 2 h. Theconsumption of the starting material was monitored by TLC(AcOEt/n-hexane 0.5:9.5). The reaction was then quenched by addingsaturated aqueous ammonium chloride solution (70 mL). The layers wereseparated and the aqueous phase was extracted with AcOEt (3×50 mL). Thecombined organic layers were dried over Na₂SO₄, gravity filtered andconcentrated under reduced pressure. The reaction residue was purifiedby silica gel flash chromatography, eluting with AcOEt/n-hexane 0.5:9.5,to provide 2.55 g of the title compound as a yellow oil in a 81% yield.

Synthesis of diethyl2-(3-(2-chlorophenyl)allyl)-2-(4-oxopent-2-yn-1-yl)malonate (EB-079)

An oven-dried 100 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with compound EB-075 (0.5 g, 1.4 mmol) and dryTHF (20 mL). The solution was cooled to −78° C. in a dry ice/acetonebath for 15 min, then LDA (0.7 mL of a 2 M heptane/THF/ethylbenzenesolution, 1.4 mmol) was added via syringe. The mixture was stirred at−78° C. for 1 h, then N-methoxy-N-methylacetamide (0.16 g, 0.16 mL, 1.54mmol) was added. The solution was warmed to room temperature and wasstirred for 4 h. The consumption of the starting material was monitoredby TLC (AcOEt/n-hexane 1:9). The reaction was quenched by addingsaturated aqueous ammonium chloride solution (40 mL). The layers wereseparated and the aqueous phase was extracted with ether (3×30 mL). Thecombined organic layers were dried over Na₂SO₄, gravity filtered andconcentrated under reduced pressure. The reaction residue was purifiedby silica gel flash chromatography, eluting with AcOEt/n-hexane 2:8, toprovide 0.47 g of the title compound as a colorless oil in a 86% yield.

¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J=7.2 Hz, 1H), 7.39 (t, J=7.7 Hz,1H), 7.36-7.14 (m, 2H), 6.98 (d, J=15.6 Hz, 1H), 6.11 (dt, J=15.6, 7.6Hz, 1H), 4.33 (q, J=7.1 Hz, 4H), 3.11 (s, 2H), 3.07 (d, J=7.6 Hz, 2H),2.40 (s, 3H), 1.36 (t, J=7.1 Hz, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 183.9, 169.2 (2C), 134.9, 132.7, 131.3,129.6, 128.7, 126.9, 126.9, 125.9, 87.7, 83.6, 62.1 (2CH₂), 56.8, 36.3,32.9, 23.4, 14.1 (2CH₃) ppm

IR (thin film) 2982, 2936, 2213, 1734, 1679, 1203 cm⁻¹

HRMS TOF MS ES+: C₂₁H₂₄O₅C1 Calculated: 391.1312. Found: 391.1299.

Synthesis of diethyl4-acetyl-8-chloro-1H-cyclopenta[b]naphthalene-2,2(3H)-dicarboxylate(EB-081)

A microwave irradiation vial (10-20 mL) was equipped with a sir bar (1.5cm) and was charged with compound EB-079 (0.3 g, 0.77 mmol) and1,2-dichlorobenzene (12.8 mL). The reaction was irradiated with stirringat 180° C. for 30 min, turning gold in color. The solution was directlycharged into a silica gel column, which was eluted with n-hexane toseparate the 1,2-dichlorobenzene and then AcOEt/n-hexane 2:8 to collectthe pure product. The title compound was isolated as a yellow oil in aquantitative yield (0.298 g). Small traces of contaminants wereobserved.

¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.53 (d,J=7.4 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 4.27-4.17 (m, 4H), 3.76 (s, 2H),3.68 (s, 2H), 2.66 (s, 3H), 1.38-1.13 (m, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 205.0, 170.9 (2C), 140.5, 136.7, 135.4,132.3, 130.7, 130.0, 126.3, 126.3, 123.7, 121.0, 62.1 (2CH₂), 60.9,40.1, 39.4, 32.3, 14.1 (2CH₃).

IR (thin film) 2981, 2935, 1731, 1697, 1253, 1185 cm⁻¹

HRMS TOF MS ES+: C₂₁H₂₂O₅Cl Calculated: 389.1156. Found: 389.1166.

Literature Preparation.

4-Methyl-N-(prop-2-yn-1-yl)benzenesulfonamide was prepared fromprop-2-yn-1-amine and 4-methylbenzene-1-sulfonyl chloride through asubstitution reaction, which was reported by Gilbertson et al. J. Org.Chem. 2007, 72, 799. (E)-1-(3-bromoprop-1-en-1-yl)-2-chlorobenzene wasprepared starting from 2-chlorobenzaldehyde via the procedure reportedby Feringa.

Synthesis ofN-(3-(2-chlorophenyl)allyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide(EB-047)

To an oven-dried, 100 mL, three-necked round-bottomed flask equippedwith a stir bar, two septa and a nitrogen gas inlet adaptor, was added4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (1.0 g, 4.8 mmol) andK₂CO₃ (2.69 g, 19.2 mmol). The flask was evaporated and refilled withnitrogen three times, then MeCN (60 mL) was added.(E)-1-(3-bromoprop-1-en-1-yl)-2-chlorobenzene (1.66 g, 7.2 mmol) wasadded dropwise via syringe, turning the solution dark yellow. Themixture was heated at reflux and stirred overnight. The consumption ofthe starting material was monitored by TLC (AcOEt/n-hexane 1:9). At theend of the reaction the solvent was removed in vacuo. The reactionresidue was taken up in saturated NaHCO₃ solution (70 mL) and extractedwith ether (3×50 mL). The combined organic layers were washed with brine(70 mL), dried over Na₂SO₄, gravity filtered and concentrated underreduced pressure. The reaction residue was purified by silica gel flashchromatography, eluting with AcOEt/n-hexane 1:9, to provide 1.35 g ofthe title compound as a light yellow solid in a 78% yield.

Synthesis ofN-(3-(2-chlorophenyl)allyl)-4-methyl-N-(4-oxopent-2-yn-1-yl)benzenesulfonamide (EB-050)

An oven-dried, 100 mL, three-necked round-bottomed flask under anitrogen atmosphere was charged with compound EB-047 (1.0 g, 2.8 mmol)and dry THF (40 mL). The solution was cooled to −78° C. in a dryice/acetone bath for 15 min, then n-BuLi (1.74 mL of a 1.6 M n-hexanesolution, 2.8 mmol) was added via syringe. The mixture was stirred at−78° C. for 1 h, then N,N-dimethylacetamide (0.18 g, 0.19 mL, 2.1 mmol)and BF₃.Et₂O (0.29 g, 0.26 mL, 2.1 mmol) were added. The solution wasstirred at −78° C. for an additional 3 h. The consumption of thestarting material was monitored by TLC (AcOEt/n-hexane 3:7). Thereaction was quenched by adding saturated aqueous ammonium chloridesolution (50 mL). The layers were separated and the aqueous phase wasextracted with ether (3×30 mL). The combined organic layers were driedover Na₂SO₄, gravity filtered and concentrated under reduced pressure.The reaction residue was purified by silica gel flash chromatography,eluting with AcOEt/n-hexane 2:8, to provide 0.48 g of the title compoundas a light yellow solid in a 43% yield.

¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=8.2 Hz, 2H), 7.53-7.40 (m, 1H),7.35-7.31 (m, 3H), 7.28-7.10 (m, 2H), 6.96 (d, J=15.7 Hz, 1H), 6.07 (dt,J=15.7, 6.8 Hz, 1H), 4.28 (s, 2H), 4.02 (d, J=6.7 Hz, 2H), 2.43 (s, 3H),2.11 (s, 3H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 183.2, 144.3, 135.5, 134.2, 133.2, 131.6,129.9 (2CH), 129.8, 129.4, 127.9 (2CH), 127.2, 127.1, 125.6, 84.9, 84.2,49.5, 36.4, 32.5, 21.6 ppm

IR (thin film) 2920, 2209, 1679, 1351, 1162 cm⁻¹

HRMS TOF MS ES+: C₂₁H₂₁NO₃SCl Calculated: 402.0931. Found: 402.0951.

Synthesis of1-(8-chloro-2-tosyl-2,3-dihydro-1H-benzo[f]isoindol-4-yl)ethanone(EB-067-A) and1-(8-chloro-2-tosyl-2,3,9,9a-tetrahydro-1H-benzo[f]isoindol-4-yl)ethanone(EB-067-B)

A microwave irradiation vial (2-5 mL) was equipped with a sir bar (1 cm)and was charged with compound EB-050 (0.07 g, 0.17 mmol) and1,2-dichlorobenzene (3 mL). The reaction was irradiated with stirring at180° C. for 10 min, turning brown in color. The solution was directlycharged into a silica gel column, which was eluted with n-hexane toseparate the 1,2-dichlorobenzene and then AcOEt/n-hexane 2:8 to collectthe pure products. The title compounds EB-067-A:EB-067-B were isolatedas a 1:2 mixture of inseparable products in a 71% yield (0.048 g).

Data for EB-067-A and EB-067-B:

¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H minor) 7.80-7.71 (m, 3H major and3H minor), 7.59 (d, J=7.4 Hz, 1H minor), 7.47-7.23 (m, 3H major and 2Hminor), 7.16 (t, J=7.8 Hz, 1H major), 7.00 (d, J=7.6 Hz, 1H major), 4.77(s, 2H minor), 4.70 (s, 2H minor), 4.55 (d, J=18.0 Hz, 1H major), 4.10(m, 1H major), 3.99 (t, J=8.1 Hz, 1H major), 3.90 (d, J=18.0 Hz, 1Hmajor), 3.38 (dd, J=15.4, 6.1 Hz, 1H major), 3.04-2.79 (m, 2H major),2.65 (s, 3H minor), 2.43 (s, 3H major), 2.39 (s, 3H minor), 2.31 (s, 3Hmajor) ppm

¹³C NMR (100 MHz, CDCl₃) δ 203.6 (minor), 200.3 (major), 148.6 (major),144.2 (minor), 144.1 (major), 136.4 (minor), 134.2 (minor), 134.0(major), 133.6 (1C major and 1C minor), 133.1 (minor), 132.9 (1C minorand 1C major), 132.7 (major), 132.5 (minor), 130.9 (minor), 130.2(minor), 130.1 (2CH minor), 130.0 (2CH major), 129.1 (2CH major), 127.9(major), 127.8 (2CH minor), 127.8 (major), 127.0 (minor), 126.9 (minor),124.2 (major), 123.8 (minor), 120.2 (minor), 53.1 (minor), 52.8 (minor),51.7 (major), 39.6 (major), 32.1 (minor), 30.1 (major), 28.6 (major),21.7 (minor), 21.6 (major), 14.3 (major).

Synthesis of1-(8-chloro-2-tosyl-2,3-dihydro-1H-benzo[f]isoindol-4-yl)ethanone(EB-051)

A microwave irradiation vial (10-20 mL) was equipped with a sir bar andwas charged with compound EB-050 (0.3 g, 0.75 mmol) and1,2-dichlorobenzene (12.4 mL). The reaction was irradiated with stirringat 180° C. for 3 h, turning black in color. The solution was directlycharged into a silica gel column, which was eluted with n-hexane toseparate the 1,2-dichlorobenzene and then AcOEt/n-hexane 2:8 to collectthe pure product. The title compound was isolated as a brown solid in a31% yield (0.093 g).

¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.78 (d, J=8.2 Hz, 2H), 7.70 (d,J=8.5 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.32 (d,J=8.0 Hz, 2H), 4.73 (s, 2H), 4.69 (s, 2H), 2.63 (s, 3H), 2.38 (s, 3H).

¹³C NMR (100 MHz, CDCl₃) δ 203.6, 144.2, 136.3, 134.1, 133.5, 133.1,132.6, 130.9, 130.2, 130.0 (2CH), 127.8 (2CH), 127.0, 126.9, 123.8,120.2, 53.1, 52.8, 32.1, 21.6.

IR (thin film) 2921, 1691, 1346, 1160 cm⁻¹

HRMS TOF MS ES+: C₂₁H₁₇NO₃SCl Calculated: 398.0618. Found: 398.0609.

Literature Preparations

The preparation of(E)-diethyl-2-(3-(2-chlorophenyl)allyl)-2-(prop-2-yn-1-yl)malonate (S1)followed the procedure reported by Brummond et al., J. Am. Chem. Soc.2012, 134, 12418-12421.

Synthesis of2-(3-(2-chlorophenyl)allyl)-2-(prop-2-yn-1-yl)propane-1,3-diol (S2)

The title compound was synthesized via a modification of the procedureoriginally reported by Malacria and co-workers. An oven-dried, 100 mLthree-necked round-bottomed flask under a nitrogen atmosphere wascharged with compound S1 (0.45 g, 1.29 mmol) and dry CH₂Cl₂ (20 mL). Thesolution was cooled to 0° C. in an ice bath for 15 min, then LiAlH₄ (1 Min Et₂O, 2.58 mL, 2.58 mmol) was added dropwise over 10 min. The mixturewas warmed to rt and stirred for 1 h. The consumption of the startingmaterial was monitored by TLC (AcOEt/n-hexane 1:1). The reaction wasquenched with sat'd aq ammonium chloride solution (50 mL). The layerswere separated and the aqueous phase was extracted with AcOEt (3×30 mL).The combined organic layers were dried over MgSO₄, gravity filtered, andconcentrated under reduced pressure. The title compound was isolated asa white solid (0.31 g, 91% yield), and was used in the next syntheticstep without further purification.

Data for S2

¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J=7.2 Hz, 1H), 7.33 (d, J=7.7 Hz,1H), 7.18 (dt, J=19.9, 7.2 Hz, 2H), 6.85 (d, J=15.7 Hz, 1H), 6.20 (dt,J=15.6, 7.7 Hz, 1H), 3.84-3.58 (m, 4H), 2.61 (s, 2H), 2.36 (d, J=7.7 Hz,2H), 2.31 (d, J=2.5 Hz, 2H), 2.08 (t, J=2.5 Hz, 1H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 135.6, 132.7, 130.1, 129.7, 128.4, 128.2,126.9, 126.9, 80.9, 71.2, 67.5 (2 CH₂), 42.8, 35.5, 21.8 ppm

IR (thin film) 3299, 2927, 1717, 1033 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₅H₁₈O₂Cl: 265.0995. found:265.0996.

Synthesis of5-(3-(2-chlorophenyl)allyl)-2,2-dimethyl-5-(prop-2-yn-1-yl)-1,3-dioxane(S3)

The title compound was synthesized via a modification of the procedureoriginally reported by Saitoh and co-workers. An oven-dried, 50 mLone-necked round-bottomed flask was charged with compound S2 (0.26 g,0.98 mmol) and acetone (10 mL). p-Toluenesulfonic acid monohydrate(PTSA) (0.019 g, 0.098 mmol) and ethyl orthoformate (0.82 g, 4.9 mmol)were added and the mixture was stirred at rt for 1 h. The consumption ofthe starting material was monitored by TLC (AcOEt/n-hexane 1:9). Thereaction was quenched with sat'd aq NaHCO₃ solution (30 mL). The layerswere separated and the aqueous phase was extracted with Et₂O (3×15 mL).The combined organic layers were dried over MgSO₄, gravity filtered, andconcentrated under reduced pressure. The reaction residue was purifiedby silica gel flash chromatography, eluting with AcOEt/n-hexane 0.5:9.5,to provide 0.27 g of the title compound as a colorless oil in 90% yield.

Data for S3

¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J=7.4 Hz, 1H), 7.34 (d, J=7.7 Hz,1H), 7.26-7.07 (m, 2H), 6.85 (d, J=15.7 Hz, 1H), 6.15 (dt, J=15.6, 7.8Hz, 1H), 3.73 (s, 4H), 2.43 (d, J=2.3 Hz, 2H), 2.38 (d, J=7.7 Hz, 2H),2.07 (s, 1H), 1.44 (s, 3H), 1.42 (s, 3H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 135.6, 132.8, 130.4, 129.8, 128.5, 127.4,127.0, 126.9, 98.4, 80.7, 71.3, 66.9 (2CH₂), 36.3, 36.2, 25.7, 22.7,22.1 ppm

IR (thin film) 3301, 2991, 2939, 2864, 2116, 1196, 1082 cm⁻¹

HRMS (TOF MS ES+) [M]⁺ calcd for C₁₈H₂₁O₂Cl: 304.1230. found: 304.1259.

Synthesis of6-(3-(2-chlorophenyl)allyl)-2,2,3,3,9,9,10,10-octamethyl-6-(prop-2-yn-1-yl)-4,8-dioxa-3,9-disilaundecane(S4)

An oven-dried 100 mL one-necked round-bottomed flask was charged withcompound S2 (0.2 g, 0.76 mmol) and DMF (15 mL). The solution was cooledto 0° C. in an ice bath for 15 min, then TBSCl (0.23 g, 1.51 mmol) andEt₃N (0.31 mL, 2.26 mmol) were added sequentially. The solution waswarmed to rt and was stirred overnight. The consumption of the startingmaterial was monitored by TLC (AcOEt/n-hexane 0.5:9.5). The reaction waspoured in n-hexanes (20 mL) and water (40 mL). The layers were separatedand the aqueous phase was extracted with n-hexane (3×20 mL). Thecombined organic layers were dried over MgSO₄, gravity filtered, andconcentrated under reduced pressure, to provide 0.30 g of the titlecompound as yellow oil in 80% yield.

Data for S4

¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J=7.2 Hz, 1H), 7.33 (d, J=7.8 Hz,1H), 7.17 (dt, J=24.5, 7.3 Hz, 2H), 6.83 (d, J=15.8 Hz, 1H), 6.23 (dt,J=15.6, 7.7 Hz, 1H), 3.59-3.29 (m, 4H), 2.31 (d, J=7.7 Hz, 2H), 2.17 (d,J=2.3 Hz, 2H), 1.98 (s, 1H), 0.91 (s, 18H), 0.06 (s, 12H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 136.1, 132.7, 129.8, 129.5, 129.3, 128.1,126.9, 126.8, 81.7, 70.3, 63.8 (2CH₂), 44.2, 34.7, 26.0 (6CH₃), 21.4,18.4 (2C), −5.3 (2CH₃), −5.4 (2CH₃) ppm

IR (thin film) 3310, 2953, 2929, 2857, 1469, 1253, 1090, 836 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₇H₄₆O₂Si₂Cl: 493.2725. found:493.2693.

Synthesis of5-(5-(3-(2-chlorophenyl)allyl)-2,2-dimethyl-1,3-dioxan-5-yl)pent-3-yn-2-one(4a)

An oven-dried 100 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with compound S3 (0.22 g, 0.72 mmol) and THF (10mL). The solution was cooled to −78° C. in a dry ice/acetone bath for 15min, then LDA (0.36 mL of a 2.0 M heptane/THF/ethylbenzene solution,0.72 mmol) was added via syringe. The mixture was stirred at −78° C. for1 h, then N-methoxy-N-methylacetamide (0.084 mL, 0.79 mmol) was added.The solution was warmed to rt and was stirred for 4 h. The consumptionof the starting material was monitored by TLC (AcOEt/n-hexane 2:8). Thereaction was quenched by adding sat'd aq ammonium chloride solution (50mL). The layers were separated and the aqueous phase was extracted withether (3×30 mL). The combined organic layers were dried over MgSO₄,gravity filtered, and concentrated under reduced pressure. The reactionresidue was purified by silica gel flash chromatography, eluting withAcOEt/n-hexane 1.5:8.5, to provide 0.18 g of the title compound as acolorless oil in a 72% yield.

Data for 4a

¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J=7.4 Hz, 1H), 7.33 (d, J=7.7 Hz,1H), 7.26-7.08 (m, 2H), 6.84 (d, J=15.7 Hz, 1H), 6.09 (dt, J=15.6, 7.8Hz, 1H), 3.77 (d, J=11.9 Hz, 2H), 3.67 (d, J=11.9 Hz, 2H), 2.66 (s, 2H),2.32-2.29 (m, 5H), 1.43 (s, 3H), 1.41 (s, 3H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 184.4, 135.3, 132.8, 130.8, 129.8, 128.6,127.0, 126.9, 126.5, 98.5, 90.3, 84.0, 66.8 (2CH₂), 36.7, 36.6, 32.9,26.7, 23.1, 20.9 ppm

IR (thin film) 2991, 2939, 2866, 2208, 1675, 1229 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₀H₂₄O₃Cl: 347.1414. found:347.1420.

Synthesis of6-(5-(3-(2-chlorophenyl)allyl)-2,2-dimethyl-1,3-dioxan-5-yl)-2,2-dimethylhex-4-yn-3-one(4b)

The title compound was synthesized via a modification of the procedureoriginally reported by Diederich and co-workers. An oven-dried 100 mLthree-necked round-bottomed flask under a nitrogen atmosphere wascharged with compound S3 (0.34 g, 1.12 mmol) and THF (30 mL). Thesolution was cooled to −78° C. in an dry ice/acetone bath for 15 min,then n-BuLi (0.7 mL of a 1.6 M n-hexane solution, 1.12 mmol) was addeddropwise over 5 min via syringe. The mixture was warmed to rt andstirred 30 min, then cooled to −78° C. and CuI (0.21 g, 1.12 mmol) wasadded. The solution was warmed to 0° C. and stirred for 30 min, thenpivaloyl chloride (0.14 mL, 1.12 mmol) was added dropwise. The mixturewas warmed to rt and stirred for an additional 2 h. The consumption ofthe starting material was monitored by TLC (AcOEt/n-hexane 1.5:8.5). Thereaction was quenched by adding sat'd aq NHCO₃ solution (50 mL). Thelayers were separated and the aqueous phase was extracted with Et₂O(3×25 mL). The combined organic layers were washed with brine (50 mL),dried over MgSO₄, gravity filtered, and concentrated under reducedpressure. The reaction residue was purified by silica gel flashchromatography, eluting with AcOEt/n-hexane 1.5:8.5, to provide 0.21 gof the title compound as a colorless oil in a 48% yield.

Data for 4b

¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J=7.4 Hz, 1H), 7.34 (d, J=7.4 Hz,1H), 7.19 (dt, J=15.7, 7.4 Hz, 2H), 6.85 (d, J=15.7 Hz, 1H), 6.11 (dt,J=15.7, 7.7 Hz, 1H), 3.78 (d, J=11.8 Hz, 2H), 3.70 (d, J=11.8 Hz, 2H),2.67 (s, 2H), 2.37 (d, J=7.7 Hz, 2H), 1.45 (s, 3H), 1.42 (s, 3H), 1.21(s, 9H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 194.0, 135.4, 132.9, 130.9, 129.8, 128.8,127.1, 127.0, 126.6, 98.6, 91.7, 81.6, 66.8 (2CH₂), 44.9, 36.9 (2CH₃),36.6, 26.3 (3CH₃), 23.3, 21.5 ppm

IR (thin film) 2968, 2867, 2208, 1667, 1154 cm⁻¹

HRMS (TOF MS ES+) [M−H]⁺ calcd for C₂₃H₂₈O₃Cl: 387.1727. found:387.1733.

Synthesis of6,6-bis(((tert-butyldimethylsilyl)oxy)methyl)-9-(2-chlorophenyl)non-8-en-3-yn-2-one(4c)

An oven-dried 100 mL three-necked round-bottomed flask under a nitrogenatmosphere was charged with compound S4 (0.21 g, 0.43 mmol) and THF (10mL). The solution was cooled to −78° C. in a dry ice/acetone bath for 15min, then LDA (0.21 mL of a 2.0 M heptane/THF/ethylbenzene solution,0.43 mmol) was added via syringe. The mixture was stirred at −78° C. for1 h, then N-methoxy-N-methylacetamide (0.051 mL, 0.48 mmol) was added.The solution was warmed to rt and was stirred for 4 h. The consumptionof the starting material was monitored by TLC (AcOEt/n-hexane 0.5:9.5).The reaction was quenched by adding sat'd aq ammonium chloride solution(50 mL). The layers were separated and the aqueous phase was extractedwith ether (3×30 mL). The combined organic layers were dried over MgSO₄,gravity filtered, and concentrated under reduced pressure. The reactionresidue was purified by silica gel flash chromatography, eluting withAcOEt/n-hexane 1:9, to provide 0.11 g of the title compound as a yellowoil in a 48% yield.

Data for 4c

¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J=7.0 Hz, 1H), 7.34 (d, J=7.7 Hz,1H), 7.26-7.07 (m, 2H), 6.83 (d, J=15.7 Hz, 1H), 6.19 (dt, J=15.6, 7.7Hz, 1H), 3.48 (d, J=1.7 Hz, 4H), 2.54-2.20 (m, 7H), 0.91 (s, 18H), 0.06(s, 12H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 184.6, 135.8, 132.8, 129.8, 129.7, 128.7,128.3, 126.9, 126.9, 91.8, 83.4, 63.9 (2CH₂), 44.8, 35.1, 33.0, 26.0(6CH₃), 22.1, 18.4 (2C), −5.39 (2CH₃), −5.45 (2CH₃) ppm

IR (thin film) 2953, 2929, 2898, 2857, 2208, 1679, 1469, 1253, 1092, 832cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₉H₄₈O₃Si₂Cl: 535.2831. found:535.2850.

Synthesis of1-(5-chloro-2′,2′-dimethyl-1,3-dihydrospiro[cyclopenta[b]naphthalene-2,5′-[1,3]dioxan]-9-yl)ethanone(5a)

To a 2-5 mL microwave irradiation vial equipped with a stir bar wasadded compound 4a (0.105 g, 0.30 mmol) in 1,2-dichlorobenzene (5 mL).The reaction was irradiated with stirring at 180° C. for 45 min untilcomplete by TLC (AcOEt/n-hexane 3:7). The solution was directly added toa silica gel column, which was eluted with n-hexane to separate the1,2-dichlorobenzene and then AcOEt/n-hexane 2:8 to collect the pureproduct. The title compound was isolated as a light yellow solid in an85% yield (0.088 g).

Data for 5a

¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.52 (d,J=7.4 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 3.92-3.57 (m, 4H), 3.05 (d, J=7.1Hz, 4H), 2.63 (s, 3H), 1.47 (d, J=5.2 Hz, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 205.3, 141.9, 137.9, 136.1, 132.2, 130.6,129.9, 126.1, 126.1, 123.6, 121.7, 98.3, 68.4 (2CH₂), 42.8, 39.5, 39.1,32.3, 24.2, 23.6 ppm

IR (thin film) 2991, 2941, 2870, 1683, 1374, 1277, 1197, 1058 cm⁻¹

HRMS (TOF MS ES+) [M-CH₃]⁺ calcd for C₁₉H₁₈O₃Cl: 329.0944. found:329.0926.

Synthesis of1-(5-chloro-2′,2′-dimethyl-1,3-dihydrospiro[cyclopenta[b]naphthalene-2,5′-[1,3]dioxan]-9-yl)-2,2-dimethylpropan-1-one(5b)

To a 10-20 mL microwave irradiation vial equipped with a stir bar wasadded compound 4b (0.21 g, 0.54 mmol) in 1,2-dichlorobenzene (10 mL).The reaction was irradiated with stirring at 180° C. for 45 min untilcomplete by TLC (AcOEt/n-hexane 2:8). The solution was directly added toa silica gel column, which was eluted with n-hexane to separate the1,2-dichlorobenzene and then AcOEt/n-hexane 2:8 to collect the pureproduct. The title compound was isolated as a light yellow solid in a47% yield (0.098 g).

Data for 5b

¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.36 (d,J=8.3 Hz, 1H), 7.27 (dd, J=15.2, 7.2 Hz, 1H), 3.80 (s, 2H), 3.69 (d,J=12.4 Hz, 2H), 3.06 (q, J=16.4 Hz, 2H), 2.89 (s, 2H), 1.46 (s, 3H),1.44 (s, 3H), 1.26 (s, 9H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 216.8, 142.0, 136.7, 136.5, 132.2, 130.4,130.3, 126.1, 125.5, 124.4, 120.5, 98.3, 68.6, 68.1, 45.4, 43.1, 39.6,39.3, 28.1 (3CH₃), 24.0, 23.9 ppm

IR (thin film) 2961, 2931, 2859, 1687, 1133, 1058 cm⁻¹

Synthesis of1-(2,2-bis(((tert-butyldimethylsilyl)oxy)methyl)-8-chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(5c)

To a 2-5 mL microwave irradiation vial equipped with a stir bar wasadded compound 4c (0.09 g, 0.17 mmol) in 1,2-dichlorobenzene (3 mL). Thereaction was irradiated with stirring at 180° C. for 45 min untilcomplete by TLC (Et₂O/n-hexane 1:9). The solution was directly added toa silica gel column, which was eluted with n-hexane to separate the1,2-dichlorobenzene and then Et₂O/n-hexane 2:8 to collect the pureproduct. The title compound was isolated as a light yellow oil in a 92%yield (0.083 g).

Data for 5c

¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.52 (d,J=7.4 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 3.57 (s, 4H), 2.97 (s, 2H), 2.92(s, 2H), 2.63 (s, 3H), 0.88 (s, 18H), 0.03 (s, 6H), 0.02 (s, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 205.6, 143.7, 139.4, 135.8, 132.1, 130.6,129.9, 125.9, 125.8, 123.6, 121.3, 65.2 (2CH₂), 51.3, 37.8, 36.9, 32.3,26.0 (6CH₃), 18.4 (2C), −5.3 (2CH₃), −5.35 (2CH₃) ppm

IR (thin film) 2953, 2895, 2855, 1699, 1463, 1253, 1101, 838 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₉H₄₆O₃Si₂Cl: 533.2674. found:533.2679.

General Procedure: Buchwald-Hartwig Couplings

An oven-dried sealed tube was equipped with a stir bar and charged with[RuPhos Palladacyle] (0.025 equiv). The tube was closed with a septum,then evacuated and refilled with nitrogen three times through a needle.LHMDS (1M solution in THF, 2 equiv) and chlorinated naphthalene (1equiv) in THF were added via syringe. Finally, the amine (1.5 equiv) inTHF was added at rt via syringe. The resulting solution was heated at85° C. in an oil bath and stirred for 3 h. The consumption of thestarting material was monitored by TLC. Once the reaction was complete,the mixture was cooled to rt, diluted with sat'd aq ammonium chloridesolution (10 mL), and then extracted with AcOEt (3×12 mL). The combinedorganic layers were dried over Na₂SO₄, gravity filtered, andconcentrated in vacuo. The crude product was purified by flashchromatography over silica gel.

Synthesis of1-(5-(dimethylamino)-2′,2′-dimethyl-1,3-dihydrospiro[cyclopenta[b]naphthalene-2,5′-[1,3]dioxan]-9-yl)ethanone(6a)

Follows general procedure (pag. 13): [RuPhos Palladacyle] (0.0015 g,0.0021 mmol), LHMDS (0.17 mL of a 1.0 M solution in THF, 0.17 mmol), 5a(0.030 g, 0.087 mmol) in THF (0.3 mL), dimethylamine (0.065 mL of a 2.0M solution in THF, 0.13 mmol). The title compound was isolated(n-hexane/AcOEt 8:2, 0.019 g, 62% yield) as a yellow solid.

Data for 5a

¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.36 (t,J=7.9 Hz, 1H), 7.07 (d, J=7.3 Hz, 1H), 3.78 (s, 4H), 3.08 (s, 2H), 3.00(s, 2H), 2.86 (s, 6H), 2.64 (s, 3H), 1.48 (d, J=2.5 Hz, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.2, 151.2, 139.8, 136.7, 136.2, 130.0,128.9, 126.3, 121.5, 119.5, 114.3, 98.3, 68.7 (2CH₂), 45.5 (2CH₃), 42.8,39.8, 39.0, 32.4, 24.2, 23.8 ppm

IR (thin film) 2989, 2938, 2856, 2784, 1693, 1197 cm⁻¹

HRMS (TOF MS ES+) [M]⁺ calcd for C₂₂H₂₇NO₃: 353.1991. found: 353.1998.

Synthesis of1-(5-(dimethylamino)-2′,2′-dimethyl-1,3-dihydrospiro[cyclopenta[b]naphthalene-2,5′-[1,3]dioxan]-9-yl)-2,2-dimethylpropan-1-one(6b)

Follows general procedure [RuPhos Palladacyle] (0.0023 g, 0.0032 mmol),LHMDS (0.26 mL of a 1.0 M solution in THF, 0.26 mmol), 5b (0.050 g, 0.13mmol) in THF (0.3 mL), dimethylamine (0.098 mL of a 2.0 M solution inTHF, 0.19 mmol). The title compound was isolated (n-hexane/AcOEt 7:3,0.030 g, 58% yield) as a yellow solid.

Data for 6b

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.13 (d,J=8.3 Hz, 1H), 7.04 (d, J=7.4 Hz, 1H), 3.83 (s, 2H), 3.77-3.60 (m, 4H),3.21-2.96 (m, 2H), 2.87 (s, 6H), 1.48 (s, 3H), 1.47 (s, 3H), 1.29 (s,9H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 217.7, 151.0, 139.8, 136.8, 135.0, 130.4,128.6, 125.6, 120.4, 120.1, 114.1, 98.2, 68.7, 68.3, 45.5 (2CH₂), 45.3,43.0, 39.8, 39.2, 28.1 (3CH₃), 24.5, 23.5 ppm

IR (thin film) 2938, 2862, 2785, 1685, 1477, 1197, 1056 cm⁻¹

HRMS (TOF MS ES+) [M]⁺ calcd for C₂₅H₃₃NO₃: 395.2460. found: 395.2469.

Synthesis of1-(2,2-bis(((tert-butyldimethylsilyl)oxy)methyl)-8-(dimethylamino)-2,3-dihydro-1H-cyclo-penta[b]naphthalen-4-yl)ethanone(6c)

Follows general procedure (pag. 13): [RuPhos Palladacyle] (0.0013 g,0.0018 mmol), LHMDS (0.15 mL of a 1.0 M solution in THF, 0.15 mmol), 5c(0.040 g, 0.075 mmol) in THF (0.3 mL), dimethylamine (0.056 mL of a 2.0M solution in THF, 0.11 mmol). The title compound was isolated(n-hexane/Et₂O 8:2, 0.029 g, 71% yield) as a yellow oil.

Data for 6c

¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.34 (t,J=7.9 Hz, 1H), 7.06 (d, J=7.3 Hz, 1H), 3.56 (s, 4H), 3.09-2.75 (m, 10H),2.62 (s, 3H), 0.88 (s, 18H), 0.02 (s, 12H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.5, 151.0, 141.4, 138.1, 136.0, 129.9,128.8, 125.9, 121.0, 119.5, 114.0, 65.2 (2CH₂), 51.2, 45.5 (2CH₃), 37.8,36.9, 32.3, 26.0 (6CH₃), 18.4 (2C), −5.3 (4CH₃) ppm

IR (thin film) 2929, 2896, 2855, 1697, 1578, 1465, 1253, 1098, 837 cm⁻¹

HRMS (TOF MS ES+) [M]⁺ calcd for C₃₁H₅₁NO₃Si₂: 541.3407. found:541.3403.

Synthesis of1-(2′,2′-dimethyl-5-(pyrrolidin-1-yl)-1,3-dihydrospiro[cyclopenta[b]naphthalene-2,5′-[1,3]dioxan]-9-yl)ethanone(6d)

Follows general procedure (pag. 13): [RuPhos Palladacyle] (0.0020 g,0.0028 mmol), LHMDS (0.23 mL of a 1.0 M solution in THF, 0.23 mmol), 5a(0.040 g, 0.12 mmol) in THF (0.3 mL), pyrrolidine (0.014 mL, 0.17 mmol).The title compound was isolated (n-hexane/AcOEt 8:2, 0.016 g, 35% yield)as a yellow solid.

Data for 6c

¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.33 (d, J=7.1 Hz, 2H), 6.99 (d,J=6.2 Hz, 1H), 3.77 (s, 4H), 3.30 (s, 4H), 3.07 (s, 2H), 2.98 (s, 2H),2.64 (s, 3H), 2.02 (s, 4H), 1.48 (s, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.3, 139.0, 136.5, 136.1, 130.2, 128.4,126.3, 122.1, 118.2, 112.1, 98.3, 68.7 (2CH₂), 53.1, 42.8 (2CH₂), 39.9,38.9, 32.4 (2CH₂), 24.8 (2CH₃), 24.4, 23.6 ppm

IR (thin film) 2988, 2939, 2854, 1692, 1575, 1197 cm⁻¹

HRMS (TOF MS ES+) [M]⁺ calcd for C₂₄H₂₉NO₃: 379.2147. found: 379.2167.

Synthesis of1-(8-(dimethylamino)-2,2-bis(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(7a)

An oven-dried 50 mL one-necked round-bottomed flask was charged withcompound 6a (0.036 g, 0.10 mmol) and THF (12 mL). HCl (5 mL of a 1 Naqueous solution) was added and the mixture was stirred at rt for 2 h.The consumption of the starting material was monitored by TLC(AcOEt/n-hexane 1:1). The reaction was basified to pH 7 by the dropwiseaddition of sat'd aq NaHCO₃. The layers were separated and the aqueousphase was extracted with ether (3×15 mL). The combined organic layerswere washed with brine (25 mL), dried over MgSO₄, gravity filtered, andconcentrated under reduced pressure to provide 0.018 g of the titlecompound as a yellow solid in 57% yield.

Data for 7a

¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.36 (t,J=7.9 Hz, 1H), 7.07 (d, J=7.2 Hz, 1H), 3.77 (s, 4H), 3.01 (s, 2H), 2.98(s, 2H), 2.87 (s, 6H), 2.63 (s, 3H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.8, 151.1, 140.3, 137.1, 136.2, 129.9,128.9, 126.2, 121.4, 119.5, 114.3, 69.1 (2CH₂), 49.7, 45.5 (2CH₃), 38.3,37.4, 32.4 ppm

IR (thin film) 3387, 2917, 2849, 1682, 1457, 1032 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₉H₂₄NO₃: 314.1756. found: 314.1771.

Synthesis of1-(8-(dimethylamino)-2,2-bis(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)-2,2-dimethylpropan-1-one(7b)

An oven-dried 25 mL one-necked round-bottomed flask was charged withcompound 6b (0.014 g, 0.035 mmol) and THF (5 mL). HCl (2 mL of a 1 Naqueous solution) was added and the mixture was stirred at rt for 1 h.The consumption of the starting material was monitored by TLC(AcOEt/n-hexane 1:1). The reaction was basified to pH 7 by the dropwiseaddition of sat'd aq NaHCO₃. The layers were separated and the aqueousphase was extracted with ether (3×15 mL). The combined organic layerswere washed with brine (25 mL), dried over MgSO₄, gravity filtered, andconcentrated under reduced pressure to provide 0.012 g of the titlecompound as a yellow solid in 96% yield.

Data for 7b

¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 7.29 (dd, J=15.3, 7.4 Hz, 1H),7.11 (d, J=8.3 Hz, 1H), 7.03 (d, J=7.4 Hz, 1H), 3.81 (q, J=10.2 Hz, 2H),3.63 (s, 2H), 3.05-2.88 (m, 4H), 2.86 (s, 6H), 2.74 (br, 2H), 1.27 (s,9H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 218.4, 150.9, 140.3, 136.7, 135.6, 130.4,128.6, 125.6, 120.4, 120.1, 114.1, 50.0 (2CH₂), 45.5 (2CH₃), 38.3, 37.7,30.5, 29.8, 28.1 (3CH₃) ppm

IR (thin film) 3412, 2927, 2869, 1684, 1476, 1030, 920 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₂H₃₀NO₃: 356.2226. found: 356.2206.

Synthesis of1-(2,2-bis(hydroxymethyl)-8-(pyrrolidin-1-yl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone(7c)

An oven-dried 50 mL one-necked round-bottomed flask was charged withcompound 6d (0.013 g, 0.034 mmol) and THF (10 mL). HCl (3 mL of a 1 Naqueous solution) was added and the mixture was stirred at rt for 1 h.The consumption of the starting material was monitored by TLC(AcOEt/n-hexane 1:1). The reaction was basified to pH 7 by the dropwiseaddition of sat'd aq NaHCO₃. The layers were separated and the aqueousphase was extracted with ether (3×15 mL). The combined organic layerswere washed with brine (25 mL), dried over MgSO₄, gravity filtered, andconcentrated under reduced pressure to provide 0.006 g of the titlecompound as a yellow solid in 52% yield.

Data for 7c

¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.31 (d, J=13.9 Hz, 2H), 6.99(d, J=4.9 Hz, 1H), 3.77 (br, s, 4H), 3.29 (br, s, 6H), 3.00 (s, 2H),2.96 (s, 2H), 2.63 (s, 3H), 2.02 (s, 4H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.7, 148.1, 139.4, 136.8, 136.1, 130.1,128.4, 126.3, 121.9, 118.16, 112.13, 69.3 (2CH₃), 53.1 (2CH₂), 49.7,38.3, 37.4, 32.4, 24.7 (2CH₂) ppm

IR (thin film) 3396, 2917, 2849, 1691, 1579, 1452, 1092 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₁H₂₆NO₃: 340.1913. found: 340.1911.

Synthesis of(8-(dimethylamino)-4-pivaloyl-2,3-dihydro-1H-cyclopenta[b]naphthalene-2,2-diyl)bis(methylene)bis(undec-10-enoate)(8)

An oven-dried, 25 mL one-necked round-bottomed flask was charged withcompound 7b (0.023 g, 0.065 mmol), DCC (0.029 g, 0.14 mmol), DMAP (0.017g, 0.14 mmol) and THF (7 mL). 10-Undecenoic acid (0.026 mL, 1.29 mmol)in THF (3 mL) was added and the mixture was stirred at rt overnight. Theconsumption of the starting material was monitored by TLC(AcOEt/n-hexane 1:9). After filtration over a short pad of celite, thereaction was quenched with sat'd aq NaHCO₃ solution (30 mL). The layerswere separated and the aqueous phase was extracted with Et₂O (3×15 mL).The combined organic layers were washed with brine (2×40 mL), dried overMgSO₄, gravity filtered, and concentrated under reduced pressure. Thereaction residue was purified by silica gel flash chromatography,eluting with AcOEt/n-hexane 0.5:9.5, to provide 0.014 g of the titlecompound as a clear yellow oil in 31% yield.

Data for 8

¹H NMR (500 MHz, CDCl₃) δ 8.06 (s, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.12 (d,J=8.4 Hz, 1H), 7.04 (d, J=7.1 Hz, 1H), 5.89-5.71 (m, 2H), 4.99 (dq,J=17.1, 1.6 Hz, 2H), 4.95-4.87 (dq, J=10.3, 1.6 Hz, 2H), 4.15 (s, 2H),4.11-4.01 (br, m, 2H), 3.05 (s, 2H), 2.93-2.88 (m, 2H), 2.87 (s, 6H),2.30-2.26 (m, 4H), 2.03 (q, J=6.9 Hz, 4H), 1.56 (br, s, 4H), 1.41-1.32(m, 4H), 1.26 (br, s, 25H) ppm

¹³C NMR (125 MHz, CDCl₃) δ 217.4, 173.8 (2C), 151.2, 139.4 (2CH), 136.8,134.9, 130.6, 128.8, 125.9, 120.5, 120.2, 114.4 (2CH₂), 100.1, 66.6,47.4, 45.6 (2CH₃), 45.5, 38.8, 38.2, 34.5, 34.1 (4CH₂), 29.9, 29.6(2CH₂), 29.5, 29.4 (2CH₂), 29.3 (4CH₂), 29.2 (2CH₂), 28.3 (3CH₃), 25.1ppm

IR (thin film) 2926, 2853, 1739, 1688, 1460, 1151 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₄₄H₆₆NO₅: 688.4941. found: 688.4947.

Literature Preparations

The preparation of tert-butyl(4-iodobutoxy)dimethylsilane (S5) followedthe procedure reported by Keck Org. Lett. 2008, 10, 4783-4786.

Synthesis of 6-((tert-butyldimethylsilyl)oxy)-N,N-dimethylhexanamide (9)

To an oven-dried 25 mL two-necked round-bottomed flask equipped with anitrogen inlet adapter, a septum, and a stir bar was addedN,N-dimethylacetamide (0.25 mL, 2.8 mmol) in THF (10 mL). The solutionwas cooled to −78° C. in a dry ice/acetone bath and LDA (1.5 mL of a 2.0M solution in heptane/THF/ethylbenzene, 3.0 mmol) was added dropwise viasyringe. The reaction was stirred at −78° C. for 45 min, then compoundS5 (0.94 g, 3.0 mmol) was added in one portion through the sidearm ofthe flask turning the reaction yellow. The mixture was warmed to rtslowly over 3 h, and then stirred at rt overnight, becoming cloudy andorange. The solution was poured into brine (20 mL), the aqueous layerwas separated and extracted with Et₂O (3×15). The combined organiclayers were dried over MgSO₄, gravity filtered, and concentrated underreduced pressure. The reaction residue was purified by silica gel flashchromatography, eluting with AcOEt/n-hexane 7:3, to provide 0.45 g ofthe title compound as a colorless oil in a 59% yield.

Data for 9

¹H NMR (400 MHz, CDCl₃) δ 3.60 (t, J=6.5 Hz, 2H), 2.99 (s, 3H), 2.93 (s,3H), 2.30 (t, J=7.6 Hz, 2H), 1.73-1.58 (m, 2H), 1.58-1.44 (m, 2H),1.44-1.28 (m, 2H), 0.88 (s, 9H), 0.03 (s, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 173.2, 63.2, 37.4, 35.5, 33.5, 32.8, 26.1(3CH₃), 25.9, 25.1, 18.5, −5.1 (2CH₃) ppm

IR (thin film) 3470, 2931, 2857, 1650, 1101, 836 cm⁻¹

HRMS (TOF MS ES+) [M]⁺ calcd for C₁₄H₃₁NO₂Si: 273.2124. found: 273.2128.

Literature Preparations

The preparation of (E)-1-chloro-2-(hept-1-en-6-yn-1-yl)benzene (10)followed the procedure reported by Brummond Org. Lett. 2012, 14,4430-4433.

Synthesis of(E)-1-((tert-butyldimethylsilyl)oxy)-13-(2-chlorophenyl)tridec-12-en-7-yn-6-one(11)

To an oven-dried 100 mL two-necked round-bottomed flask equipped with anitrogen inlet adapter, a septum, and a stir bar was added compound 10(0.90 g, 4.4 mmol) in THF (10 mL). The solution was cooled to −78° C. ina dry ice/acetone bath and n-butyllithium (2.75 mL of a 1.6 M solutionin hexanes, 4.4 mmol) was added dropwise via syringe turning thereaction yellow. The solution was stirred at −78° C. for 1 h, thencompound 9 (1.1 g, 3.9 mmol) in THF (10 mL) followed by borontrifluoride diethyl etherate (0.52 mL, 5.8 mmol) were added dropwise viasyringe. The mixture was stirred at −78° C. for an additional 1 h, thenwarmed to −20° C. and quenched with sat'd aq ammonium chloride solution(30 mL). The aqueous layer was extracted with Et₂O (2×20 mL). Thecombined organic layers were washed with brine (30 mL), dried overMgSO₄, gravity filtered, and concentrated under reduced pressure. Thecrude product was purified by silica gel flash column chromatography,eluting with AcOEt/n-hexane 0.5:9.5, to provide 0.98 g of the titlecompound as a colorless oil in a 58% yield.

Data for 11

¹H NMR (400 MHz, CDCl₃) δ 7.49 (dd, J=7.5, 1.9 Hz, 1H), 7.33 (dd, J=7.5,1.7 Hz, 1H), 7.25-7.06 (m, 2H), 6.80 (d, J=15.8 Hz, 1H), 6.16 (dt,J=15.8, 7.0 Hz, 1H), 3.60 (t, J=6.4 Hz, 2H), 2.54 (t, J=7.4 Hz, 2H),2.47-2.33 (m, 4H), 1.87-1.72 (m, 2H), 1.72-1.59 (m, 2H), 1.59-1.43 (m,2H), 1.43-1.26 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H) ppm.

¹³C NMR (100 MHz, CDCl₃) δ 188.3, 135.7, 132.8, 132.0, 129.7, 128.3,127.6, 126.9, 126.8, 93.6, 81.4, 63.0, 45.7, 32.7, 32.3, 27.3, 26.1,25.4 (3CH₃), 24.1, 18.5, 18.5, −5.1 (2CH₃) ppm

IR (thin film) 2931, 2857, 2211, 1673, 1101, 835 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₅H₃₈O₂SiCl: 433.2330. found:433.2309.

Synthesis of6-((tert-butyldimethylsilyl)oxy)-1-(8-chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)hexan-1-one(S6)

To a 10-20 mL microwave irradiation vial equipped with a stir bar wasadded compound 11 (0.35 g, 0.81 mmol) in DCE (13 mL). The reaction wasirradiated with stirring at 180° C. for 180 min until complete by TLC(AcOEt/n-hexane 0.5:9.5). The solution turned golden in color. Themixture was then transferred to a vial, concentrated under reducedpressure, and dried under vacuum to yield the title compound as a brownoil (0.34 g, 97% yield).

Data for S6

¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.52 (d,J=7.4 Hz, 1H), 7.32 (t, J=7.9 Hz, 1H), 3.61 (t, J=6.3 Hz, 2H), 3.11 (t,J=7.3 Hz, 2H), 3.01 (t, J=7.3 Hz, 2H), 2.89 (t, J=7.4 Hz, 2H), 2.18 (p,J=7.3 Hz, 2H), 1.79 (p, J=7.4 Hz, 2H), 1.63-1.50 (m, 2H), 1.48-1.42 (m,2H), 0.88 (s, 9H), 0.04 (s, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 208.8, 144.9, 140.2, 135.4, 132.2, 130.5,130.0, 125.9, 125.8, 123.6, 120.4, 63.1, 44.9, 32.8, 31.9, 26.2, 26.1(3CH₃), 25.8 (2CH₂), 23.9, 18.5, −5.1 (2CH₃) ppm

IR (thin film) 2931, 2856, 1697, 1101 cm⁻¹

HRMS (TOF MS ES+)

[M]⁺ calcd for C₂₅H₃₅O₂SiCl: 430, 2095. found: 430,2088.

Synthesis of6-((tert-butyldimethylsilyl)oxy)-1-(8-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)hexan-1-one(12)

Follows general procedure: [RuPhos Palladacyle] (0.0033 g, 0.0045 mmol),LHMDS (0.36 mL of a 1.0 M solution in THF, 0.36 mmol), S6 (0.078 g,0.018 mmol) in THF (0.5 mL), dimethylamine (0.014 mL of a 2.0 M solutionin THF, 0.027 mmol). The title compound was isolated (n-hexane/Et₂O9.8:0.2, 0.040 g, 53% yield) as a yellow oil.

Data for 12

¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.33 (d, J=4.1 Hz, 2H), 7.05 (t,J=4.1 Hz, 1H), 3.62 (t, J=6.3 Hz, 2H), 3.08 (t, J=7.2 Hz, 2H), 2.98 (t,J=7.3 Hz, 2H), 2.91-2.88 (m, 2H), 2.87 (s, 6H), 2.17 (dp, J=14.5, 7.2Hz, 2H), 1.80 (p, J=7.5 Hz, 2H), 1.56 (dd, J=14.2, 6.7 Hz, 2H), 1.44 (p,J=7.4, 6.9 Hz, 2H), 0.89 (s, 9H), 0.04 (s, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 209.6, 151.1, 142.6, 138.9, 135.6, 129.9,128.6, 125.8, 120.0, 119.5, 113.9, 63.2, 45.5 (2CH₃), 44.9, 32.8, 31.8(2CH₂), 26.2, 26.1 (3CH₃), 25.8, 23.9, 18.5, −5.1 (2CH₃) ppm

IR (thin film) 2932, 2856, 1696, 1459, 1099, 835 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₇H₄₂NO₂SiCl: 440.2985. found:440.2959.

Synthesis of1-(8-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)-6-hydroxyhexan-1-one(13)

An oven-dried 25 mL one-necked round-bottomed flask was charged withcompound 12 (0.040 g, 0.091 mmol) and THF (15 mL). TBAF (0.18 mL of a1.0 M THF solution, 0.18 mmol) was added and the mixture was stirred atrt for 3 h. The consumption of the starting material was monitored byTLC (AcOEt/n-hexane 1:1). The solution was then concentrated underreduced pressure and the reaction residue was purified by silica gelflash column chromatography, eluting with AcOEt/n-hexane 6:4, to provide0.027 g of the title compound as a yellow oil in a 91% yield.

Data for 13

¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.32 (d, J=3.4 Hz, 2H), 7.05 (s,1H), 3.66 (t, J=6.4 Hz, 2H), 3.07 (q, J=9.9, 8.6 Hz, 2H), 3.02-2.92 (m,2H), 2.87 (s, 6H), 2.15 (p, J=7.2 Hz, 2H), 1.81 (p, J=7.4 Hz, 2H), 1.62(p, J=6.6 Hz, 3H), 1.48 (p, J=7.4, 7.0 Hz, 4H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 209.6, 151.1, 142.6, 138.9, 135.4, 129.9,128.6, 125.9, 120.1, 119.4, 113.9, 62.8, 45.5 (2CH₃), 44.8, 32.8, 32.7,31.8, 26.2, 25.6, 23.7 ppm

IR (thin film) 3391, 2937, 2862, 1692, 1454, 1050 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺: C₂₁H₂₈O₂N, 326.2120. Found: 326.2111.

Literature Preparations

The preparation of4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzaldehyde (S7) followed theprocedure reported by Abel Bioorg. Med. Chem. Lett. 2010, 20, 491-4917.

Synthesis oftert-butyl(2-(4-(2,2-dibromovinyl)phenoxy)ethoxy)dimethylsilane (S8)

The title compound was synthesized via a modification of the procedureoriginally reported by Lee and co-workers. An oven-dried 250 mLone-necked round-bottomed flask was charged with compound CBr₄ (0.5 g,1.5 mmol) and dry CH₂Cl₂ (120 mL). The solution was cooled to 0° C. inan ice bath for 15 min, then PPh₃ (1.4 g, 5.5 mmol) was added in oneportion, turning the reaction yellow. The mixture was stirred at 0° C.for 30 min, then compound S7 (1.49 g, 5.3 mmol) in dry CH₂Cl₂ (20 mL)was added dropwise, turning the solution light yellow. The reaction wasstirred at 0° C. for an additional 15 min. The consumption of thestarting material was monitored by TLC (AcOEt/n-hexane 1:9). Thereaction mixture was filtered through a short pad of silica gel andconcentrated under reduced pressure to provide 1.34 g of the titlecompound as a yellow oil in a 58% yield.

Data for S8

¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J=8.4 Hz, 2H), 7.40 (s, 1H), 6.90 (d,J=8.5 Hz, 2H), 4.05 (t, J=4.9 Hz, 2H), 3.97 (t, J=4.9 Hz, 2H), 0.91 (s,9H), 0.10 (s, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 159.2, 136.5, 129.9 (2CH), 127.9, 114.5(2CH), 87.3, 69.5, 62.1, 26.1 (3CH₃), 18.6, −5.0 (2CH₃) ppm

IR (thin film) 2952, 2928, 1606, 1508, 1253, 832 cm⁻¹

HRMS (TOF MS ES+) [M]⁺ calcd for C₁₆H₂₄O₂SiBr₂ 433.9912. found:433.9924.

Synthesis of tert-butyl(2-(4-ethynylphenoxy)ethoxy)dimethylsilane (S9)

The title compound was synthesized via a modification of the procedureoriginally reported by Lee and co-workers.⁸ To an oven-dried 100 mLtwo-necked round-bottomed flask equipped with a nitrogen inlet adapter,a septum, and a stir bar was added compound S8 (0.46 g, 1.05 mmol) inTHF (30 mL). The solution was cooled to −78° C. in a dry ice/acetonebath and n-butyllithium (2.6 mL of a 1.6 M solution in hexanes, 4.2mmol) was added dropwise via syringe turning the reaction yellow. Theconsumption of the starting material was monitored by TLC(AcOEt/n-hexane 0.2:9.8). The mixture was stirred at −78° C. for anadditional 1 h, then warmed to −20° C. and quenched with sat'd aqammonium chloride solution (40 mL). The aqueous layer was extracted withEt₂O (3×30 mL). The combined organic layers were washed with brine (50mL), dried over MgSO₄, gravity filtered, and concentrated under reducedpressure. The crude product was purified by silica gel flash columnchromatography, eluting with AcOEt/n-hexane 0.2:9.8, to provide 0.22 gof the title compound as a yellow oil in a 76% yield.

Data for S9

¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz,2H), 4.04 (t, J=4.9 Hz, 2H), 3.96 (t, J=4.8 Hz, 2H), 2.99 (s, 1H), 0.90(s, 9H), 0.09 (s, 6H) ppm.

¹³C NMR (100 MHz, CDCl₃) δ 159.5, 133.7 (2CH), 114.7 (2CH), 114.3, 83.8,75.8, 69.5, 62.1, 26.0 (3CH₃), 18.6, −5.1 (2CH₃) ppm

IR (thin film) 3317, 2955, 2930, 2108, 1507, 1253, 1109 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₆H₂₅O₂Cl: 277.1624. found:277.1614.

Literature Preparations

The preparation of (E)-5-(4-chlorophenyl)-N,N-dimethylpent-4-enamide(S10) followed the procedure reported by Brummond.

Synthesis of(E)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)-7-(4-chlorophenyl)hept-6-en-1-yn-3-one(14a)

To an oven-dried 25 mL two-necked round-bottomed flask equipped with anitrogen inlet adapter, a septum, and a stir bar was added compound S9(0.22 g, 0.80 mmol) in THF (3 mL). The solution was cooled to −78° C. ina dry ice/acetone bath and n-butyllithium (0.45 mL of a 1.6 M solutionin hexanes, 0.72 mmol) was added dropwise via syringe turning thereaction yellow. The solution was stirred at −78° C. for 1 h, thencompound S10 (0.17 g, 0.73 mmol) in THF (3 mL) followed by borontrifluoride diethyl etherate (0.14 mL, 1.10 mmol) were added dropwisevia syringe. The mixture was stirred at −78° C. for an additional 1 h,then warmed to −20° C. and quenched with sat'd aq ammonium chloridesolution (20 mL). The aqueous layer was extracted with Et₂O (3×20 mL).The combined organic layers were washed with brine (30 mL), dried overMgSO₄, gravity filtered, and concentrated under reduced pressure. Thecrude product was purified by silica gel flash column chromatography,eluting with AcOEt/n-hexane 0.5:9.5, to provide 0.11 g of the titlecompound as a white solid in a 30% yield.

Data for 14a

¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J=8.4 Hz, 2H), 7.26 (m, 4H), 6.91 (d,J=8.4 Hz, 2H), 6.42 (d, J=15.8 Hz, 1H), 6.23 (dd, J=14.9, 7.7 Hz, 1H),4.08 (t, J=4.8 Hz, 2H), 3.99 (t, J=4.7 Hz, 2H), 2.85 (t, J=7.2 Hz, 2H),2.65 (q, J=6.9 Hz, 2H), 0.92 (s, 9H), 0.11 (s, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 186.9, 161.3, 135.9, 135.2 (2CH), 132.8,130.1, 129.1, 128.8 (2CH), 127.4 (2CH), 115.1 (2CH), 111.7, 92.6, 87.9,69.7, 61.9, 44.9, 27.6, 26.0 (3CH₃), 18.5, −5.1 (2CH₃) ppm

IR (thin film) 2929, 2855, 2194, 1653, 1254, 833 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₇H₃₄O₃SiCl: 469.1966. found:469.1943.

Literature Preparations

The preparation of (E)-1-(3-bromoprop-1-en-1-yl)-4-chlorobenzene (S11)followed the procedure reported by Brummond.

Synthesis of (E)-5-(4-chlorophenyl)-N-methoxy-N-methylpent-4-enamide(S12)

To an oven-dried 50 mL two-necked round-bottomed flask equipped with anitrogen inlet adapter, a septum, and a stir bar was addedN-methoxy-N-methylacetamide (1.3 mL, 12.0 mmol) in THF (10 mL). Thesolution was cooled to −78° C. in a dry ice/acetone bath and LDA (6.0 mLof a 2.0 M solution in heptane/THF/ethylbenzene, 12.0 mmol) was addeddropwise via syringe. The reaction was stirred at −78° C. for 45 min,then compound S11 (2.60 g, 11.0 mmol) in THF (5 mL) was added in oneportion through the sidearm of the flask turning the reaction yellow.The mixture was warmed to rt slowly over 3 h, and then stirred at rtovernight, becoming orange. The solution was poured into brine (20 mL),the aqueous layer was separated and extracted with Et₂O (3×15). Thecombined organic layers were dried over MgSO₄, gravity filtered, andconcentrated under reduced pressure. The reaction residue was purifiedby silica gel flash chromatography, eluting with AcOEt/n-hexane 2.5:7.5,to provide 2.46 g of the title compound as a light yellow oil in 88%yield.

Data for S12

¹H NMR (400 MHz, CDCl₃) δ 7.34-7.19 (m, 4H), 6.40 (d, J=15.9 Hz, 1H),6.24 (dt, J=15.8, 6.5 Hz, 1H), 3.69 (s, 3H), 3.19 (s, 3H), 2.66-2.57 (m,2H), 2.57-2.46 (m, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 173.7, 136.1, 132.6, 130.2, 129.5, 128.6(2CH), 127.3 (2CH), 61.3, 32.2, 31.6, 27.9 ppm

IR (thin film) 3486, 3026, 2963, 2936, 1664, 1490, 1416, 1091, 995 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₁₃H₁₇NO₂Cl 254.0948. found:254.0957.

Literature Preparations

The preparation of tert-butyl((4-ethynylbenzyl)oxy)dimethylsilane (S13)followed the procedure reported by Allen J. Am. Chem. Soc. 2009, 131,12560-12561.

Synthesis of(E)-1-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-7-(4-chlorophenyl)hept-6-en-1-yn-3-one(14b)

To an oven-dried 25 mL two-necked round-bottomed flask equipped with anitrogen inlet adapter, a septum, and a stir bar was added compound S13(0.71 g, 2.88 mmol) in THF (10 mL). The solution was cooled to −78° C.in a dry ice/acetone bath and LDA (1.56 mL of a 2.0 Mheptane/THF/ethylbenzene solution, 3.14 mmol) was added dropwise viasyringe turning the reaction brown. The solution was stirred at −78° C.for 45 min, then compound S12 (0.66 g, 2.62 mmol) in THF (5 mL) wasadded dropwise via syringe. The mixture was stirred at −78° C. for 3 h,then warmed to −20° C. and quenched with sat'd aq ammonium chloridesolution (20 mL). The aqueous layer was extracted with Et₂O (3×20 mL).The combined organic layers were washed with brine (30 mL), dried overMgSO₄, gravity filtered, and concentrated under reduced pressure. Thecrude product was purified by silica gel flash column chromatography,eluting with AcOEt/n-hexane 0.5:9.5, to provide 0.61 g of the titlecompound as a white solid in a 53% yield.

Data for 14b

¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J=7.8 Hz, 2H), 7.35 (d, J=7.8 Hz,2H), 7.26 (br s, 4H), 6.42 (d, J=15.8 Hz, 1H), 6.22 (dt, J=15.4, 6.7 Hz,1H), 4.77 (s, 2H), 2.86 (t, J=7.2 Hz, 2H), 2.65 (q, J=7.0 Hz, 2H), 0.96(s, 9H), 0.12 (s, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 187.0, 144.9, 135.9, 133.2 (2CH), 132.9,130.1, 129.0, 128.8 (2CH), 127.4 (2CH), 126.2 (2CH), 118.3, 91.8, 87.8,64.6, 45.0, 27.5, 26.0 (3CH₃), 18.5, −5.2 (2CH₃) ppm

IR (thin film) 2920, 1706, 1601, 1403, 1146 cm⁻¹

HRMS TOF MS ES+[M]⁺: C₂₆H₃₁O₂SiCl Calculated: 438.1782. Found: 438.1766.

Synthesis of9-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)-7-chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one(S14)

To a 2-5 mL microwave irradiation vial equipped with a stir bar wasadded compound 14a (0.057 g, 0.12 mmol) in 1,2-dichlorobenzene (2 mL).The reaction was irradiated with stirring at 225° C. for 60 min untilcomplete by TLC (AcOEt/n-hexane 2:8). The solution was directly added toa silica gel column, which was eluted with n-hexane to separate the1,2-dichlorobenzene and then AcOEt/n-hexane 2.5:8.5 to collect the pureproduct. The title compound was isolated as a yellow solid in an 89%yield (0.050 g).

Data for S14

¹H NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.72 (s,1H), 7.49 (d, J=8.7 Hz, 1H), 7.20 (d, J=8.2 Hz, 2H), 7.06 (d, J=8.2 Hz,2H), 4.15 (t, J=5.1 Hz, 2H), 4.05 (t, J=5.0 Hz, 2H), 3.37-3.21 (m, 2H),2.80-2.67 (m, 2H), 0.95 (s, 9H), 0.15 (s, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 205.8, 158.9, 148.6, 139.2, 135.1, 133.3,132.0, 131.8, 131.1 (2CH), 129.3, 129.2, 127.5, 127.3, 124.4, 114.3(2CH), 69.3, 62.3, 37.6, 26.1 (3CH₃), 24.8, 18.6, −4.9 (2CH₃) ppm

IR (thin film) 2928, 2856, 1711, 1598, 1250, 1107, 836 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₇H₃₂O₃SiCl: 467.1809. found:467.1804.

Synthesis of9-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)-7-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one(S15)

Follows general procedure: [RuPhos Palladacycle] (0.0019 g, 0.0026mmol), LHMDS (0.20 mL of a 1.0 M solution in THF, 0.20 mmol), S14 (0.048g, 0.10 mmol) in THF (0.3 mL), dimethylamine (0.08 mL of a 2.0 Msolution in THF, 0.15 mmol). The title compound was isolated(n-hexane/Et₂O 8:2, 0.026 g, 55% yield) as a yellow oil.

Data for S14

¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J=8.1 Hz, 2H), 7.34-7.23 (m, 3H),7.07 (d, J=8.0 Hz, 2H), 6.81 (s, 1H), 4.18 (t, J=5.0 Hz, 2H), 4.07 (t,J=5.0 Hz, 2H), 3.29-3.19 (m, 2H), 2.93 (s, 6H), 2.80-2.66 (m, 2H), 0.98(s, 9H), 0.18 (s, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.7, 158.4, 148.5, 144.7, 137.5, 134.0,131.3 (2CH), 131.0, 130.6, 129.2, 128.5, 123.9, 119.1, 114.2 (2CH),106.6, 69.3, 62.3, 40.7 (2CH₃), 37.8, 26.1 (3CH₃), 24.6, 18.6, −5.0(2CH₃) ppm

IR (thin film) 2928, 2856, 1709, 1615, 1134, 1110 cm⁻¹

HRMS (TOF MS ES+) [M]⁺ calcd for C₂₉H₃₇NO₃Si: 475.2543. found: 475.2530.

Synthesis of7-(dimethylamino)-9-(4-(2-hydroxyethoxy)phenyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one(15a)

An oven-dried 25 mL one-necked round-bottomed flask was charged withcompound S15 (0.026 g, 0.053 mmol) and THF (10 mL). TBAF (0.11 mL of a1.0 M THF solution, 0.11 mmol) was added and the mixture was stirred atrt for 1 h. The consumption of the starting material was monitored byTLC (AcOEt/n-hexane 4:6). The solution was then concentrated underreduced pressure and the reaction residue was purified by silica gelflash column chromatography, eluting with AcOEt/n-hexane 7:3, to provide0.014 g of the title compound as an orange solid in a 73% yield.

Data for 15a

¹H NMR (400 MHz, CDCl₃) δ 7.76-7.74 (br, m, 2H), 7.29-7.23 (br, m, 3H),7.05 (d, J=8.1 Hz, 2H), 6.75 (s, 1H), 4.19 (d, J=4.2 Hz, 2H), 4.03 (br,s, 2H), 3.27-3.18 (m, 2H), 2.90 (s, 6H), 2.74-2.63 (m, 3H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 205.1, 158.0, 148.5, 144.7, 137.3, 133.9,131.4, 131.2 (2CH), 130.7, 129.7, 128.5, 124.0, 119.2, 114.2 (2CH),106.4, 69.2, 61.8, 40.8 (2CH₃), 37.8, 24.6 ppm

IR (thin film) 3399, 2919, 2851, 1697, 1512, 1243 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₃H₂₄NO₃: 362.1756. found: 362.1756.

Synthesis of9-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-7-chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one(S16)

To a 10-20 mL microwave irradiation vial equipped with a stir bar wasadded compound 14b (0.18 g, 0.41 mmol) in 1,2-dichlorobenzene (10 mL).The reaction was irradiated with stirring at 225° C. for 60 min untilcomplete by TLC (AcOEt/n-hexane 1:9). The solution was directly added toa silica gel column, which was eluted with n-hexane to separate the1,2-dichlorobenzene and then AcOEt/n-hexane 1:9 to collect the pureproduct. The title compound was isolated as a white solid in aquantitative yield (0.19 g).

Data for S16

¹H NMR (300 MHz, CDCl₃) δ 7.64 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.46 (s,1H), 7.34-7.22 (m, 4H), 7.03 (d, J=7.8 Hz, 2H), 4.69 (s, 2H), 3.17-2.97(m, 2H), 2.61-2.37 (m, 2H), 0.78 (d, J=6.7 Hz, 9H), −0.03 (s, 6H) ppm

¹³C NMR (75 MHz, CDCl₃) δ 205.6, 148.5, 141.2, 139.2, 135.0, 134.0,133.1, 132.1, 131.8, 129.7 (2CH), 129.2 (2CH), 127.2, 125.9 (2CH),124.5, 65.0, 37.5, 26.1 (3CH₃), 24.8, 18.6, −5.1 (2CH₃) ppm

IR (thin film) 2952, 2928, 2854, 1717, 1084, 838 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₆H₃₀O₂SiCl: 437.1704. found:437.1682.

Synthesis of9-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-7-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one(S17)

Follows general procedure: [RuPhos Palladacycle] (0.004 g, 0.0055 mmol),LHMDS (0.44 mL of a 1.0 M solution in THF, 0.44 mmol), S16 (0.096 g,0.22 mmol) in THF (0.5 mL), dimethylamine (0.16 mL of a 2.0 M solutionin THF, 0.033 mmol). The title compound was isolated (AcOEt/n-hexane2:8, 0.051 g, 52% yield) as a yellow solid.

Data for S17

¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J=6.4 Hz, 2H), 7.45 (d, J=7.7 Hz,2H), 7.28-7.26 (br m, 3H), 6.71 (s, 1H), 4.88 (s, 2H), 3.34-3.13 (m,2H), 2.88 (s, 6H), 2.78-2.62 (m, 2H), 0.97 (s, 9H), 0.14 (s, 6H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.6, 148.5, 144.6, 140.5, 137.6, 135.7,133.8, 131.3, 130.6, 129.7 (2CH), 128.5, 125.9 (2CH), 124.0, 119.2,106.5, 65.4, 40.7 (2CH₃), 37.8, 26.2 (3CH₃), 24.6, 18.6, −4.9 (2CH₃) ppm

IR (thin film) 2927, 2952, 2854, 1710, 1602, 1085, 838 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₈H₃₆NO₂Si: 446.2515. found:446.2514.

Synthesis of7-(dimethylamino)-9-(4-(hydroxymethyl)phenyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one(15b)

An oven-dried 25 mL one-necked round-bottomed flask was charged withcompound S17 (0.036 g, 0.081 mmol) and THF (10 mL). TBAF (0.16 mL of a1.0 M THF solution, 0.16 mmol) was added and the mixture was stirred atrt for 1 h. The consumption of the starting material was monitored byTLC (AcOEt/n-hexane 1:1). The solution was then concentrated underreduced pressure and the reaction residue was purified by silica gelflash column chromatography, eluting with AcOEt/n-hexane 6:4, to provide0.026 g of the title compound as a orange solid in a 97% yield.

Data for 15b

¹H NMR (400 MHz, CDCl₃) δ 7.73-7.69 (m, 2H), 7.43 (d, J=7.6 Hz, 2H),7.31-7.24 (m, 3H), 6.65 (s, 1H), 4.75 (s, 2H), 3.25-3.09 (m, 2H), 2.82(s, 6H), 2.71-2.54 (m, 2H), 1.90 (br s, 1H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.8, 148.4, 144.7, 140.0, 137.3, 136.5,133.6, 131.3, 130.7, 130.0 (2CH), 128.6, 126.7 (2CH), 124.2, 119.2,106.5, 65.6, 40.8 (2CH₃), 37.8, 24.6 ppm

IR (thin film) 3397, 2920, 2851, 1704, 1601, 1425, 1146 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₂H₂₁NO₂: 331.1572. found: 331.1567.

Literature Preparations

The preparation of3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione (S18) followedthe procedure reported by Tew Angew. Chem. Int. Ed. 2012, 45, 7526-7530.

Synthesis of2-(4-(6-dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)dione (16)

The title compound was synthesized via a modification of the procedureoriginally reported by Tew and co-workers.¹⁰ An oven-dried 25 mLtwo-necked round-bottomed flask equipped with a nitrogen inlet adapter,a septum, and a stir bar was charged with compound 15b (0.024 g, 0.072mmol) in THF (5 mL), compound S18 (0.012 g, 0.072 mmol), and PPh₃ (0.019g, 0.072 mmol). The resulting mixture was cooled to 0° C. in an ice baththen DIAD (diisopropyl azodicarboxylate) (28 μL, 0.144 mmol) was added.The ice bath was removed and the reaction was stirred at rt for 3 h. Thesolution was then concentrated under reduced pressure and the reactionresidue was purified by silica gel flash column chromatography, elutingwith AcOEt/n-hexane 6:4, to provide 0.022 g of the title compound as aorange solid in a 65% yield.

Data for 16

¹H NMR (400 MHz, CDCl₃) δ 7.73-7-70 (m, 2H), 7.42 (d, J=7.6 Hz, 2H),7.26 (t, J=8.7 Hz, 3H), 6.53 (s, 1H), 6.50 (s, 2H), 5.28 (s, 2H), 4.76(s, 2H), 3.21-3.18 (m, 2H), 2.95 (s, 2H), 2.86 (s, 6H), 2.77-2.55 (m,2H) ppm

¹³C NMR (100 MHz, CD₂Cl₂) δ 206.6, 176.5 (2C), 164.7, 148.8, 144.9,137.1, 136.9 (2CH), 135.7, 133.9, 130.7, 130.5 (2CH), 128.9, 127.8(2CH), 122.4, 119.3, 106.1, 81.5 (2CH), 48.1 (2CH), 41.7, 40.6 (2CH₃),36.8, 24.8, 18.8 ppm

IR (thin film) 2920, 2360, 1772, 1702, 1601, 1340, 1171 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₃₀H₂₇N₂O₄: 479.1971. found:479.1974.

Synthesis of1-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzyl)-1H-pyrrole-2,5-dione(17)

An oven-dried 25 mL one-necked round-bottomed flask equipped with acondenser and a stir bar was charged with compound 16 (0.014 g, 0.027mmol) in anisole (2 mL). The solution was warmed at 145° C. and stirredfor 1 h. The solution was directly added to a silica gel column, whichwas eluted with n-hexane to separate the anisole and then AcOEt/n-hexane1:1 to collect the pure product. The title compound was isolated as ayellow solid in a 75% yield (0.009 g).

Data for 17

¹H NMR (500 MHz, CDCl₃) δ 7.74 (d, J=9.2 Hz, 2H), 7.46 (d, J=8.0 Hz,2H), 7.30-7.21 (m, 3H), 6.75 (s, 2H), 6.63 (d, J=2.3 Hz, 1H), 4.79 (s,2H), 3.34-3.11 (m, 2H), 2.87 (s, 6H), 2.76-2.52 (m, 2H) ppm

¹³C NMR (125 MHz, CDCl₃) δ 206.6, 170.6 (2C), 148.6, 144.6, 136.9,136.8, 135.2 (2CH), 134.4, 133.7, 131.3, 130.6, 130.2 (2CH), 128.6,128.2 (2CH), 124.3, 119.2, 106.2, 41.6, 40.7 (2CH₃), 37.7, 24.6 ppm

IR (thin film) 2920, 1706, 1601, 1403, 1343, 1146 cm⁻¹

HRMS (TOF MS ES+) [M]⁺ calcd for C₂₆H₂₂N₂O₃: 410.1630. found: 410.1638.

Literature Preparations

The preparation of N-Boc-L-cysteine ethyl ester (S19) followed theprocedure reported by Stanitzek Synthesis 2006, 20, 3367-3369.

Synthesis of ethyl2-((tert-butoxycarbonyl)amino)-3-((1-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzyl)-2,5-dioxopyrrolidin-3-yl)thio)propanoate(18)

An oven-dried 25 mL one-necked round-bottomed flask equipped with aseptum and a stir bar was charged with compound 17 (0.006 g, 0.015 mmol)in CH₂Cl₂/MeOH 1:1 (5 mL). N-Boc-L-cysteine ethyl ester (0.0036 g, 0.015mmol) was added in one portion and the mixture mas stirred at rt for 10min. The consumption of the starting material was monitored by TLC(AcOEt/n-hexane 1:1). The solution was then concentrated under reducedpressure and the reaction residue was purified by silica gel flashcolumn chromatography, eluting with AcOEt/n-hexane 1:1, to provide 0.006g of the title compound as a 1:1 mixture of two inseparablediastereomers (d1 and d2) in a 60% yield.

Data for 18

¹H NMR (500 MHz, CDCl₃) δ 7.74-7.73 (m, 4H, d1 and d2), 7.49-7.47 (m,4H, d1 and d2), 7.27-7.26 (m, 6H, d1 and d2), 6.61 (t, J=3.5 Hz, 2H, d1and d2), 5.66 (d, J=7.9 Hz, 1H, d1), 5.47 (d, J=7.9 Hz, 1H, d2),4.91-4.67 (m, 4H, d1 and d2), 4.59-4.55 (m, 2H, d1 and d2), 4.22 (qd,J=7.1, 1.8 Hz, 4H, d1 and d2), 4.15-4.08 (m, 1H, d1), 3.95 (d, br J=6.3Hz, 1H, d1), 3.88 (dd, J=9.1, 3.6 Hz, 1H, d2), 3.54 (dd, J=13.7, 4.0 Hz,1H, d1), 3.42 (dd, J=14.0, 5.9 Hz, 1H, d2), 3.27-3.06 (m, 6H, d1 andd2), 3.06-2.93 (m, 1H, d2, d1 and d2), 2.87 (s, 12H, d1 and d2), 2.68(dd, J=6.4, 5.0 Hz, 4H, d1 and d2), 2.57-2.42 (m, 2H, d1 and d2), 1.42(s, 18H, d1 and d2), 1.27 (t, J=7.1 Hz, 6H, d1 and d2) ppm.

¹³C NMR (125 MHz, CDCl₃) δ 206.8, 176.5, 176.4, 174.2, 171.0, 148.6,144.6, 137.2, 136.9, 134.4, 133.7, 131.3, 130.7 (2CH), 130.3, 128.7,128.6 (2CH), 124.4, 119.3, 106.2, 80.4, 62.2, 42.9, 40.8 (2CH₃), 39.0,37.6, 32.1, 29.9, 28.5, 24.7, 22.9 (3CH₃), 14.4 ppm

IR (thin film) 3362, 2924, 1706, 1602, 1509, 1341, 1166 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₃₆H₄₂N₃O₇S: 660.2743. found:660.2736.

Synthesis of4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzaldehyde(19)

An oven-dried 25 mL one-necked round-bottomed flask equipped with aseptum and a stir bar was charged with Dess-Martin periodinane (DMP,0.063 g, 0.15 mmol) in dry CH₂Cl₂ (5 mL). The solution was cooled to 0°C. in an ice bath for 10 min, compound 15b (0.045 g, 0.14 mmol) in dryCH₂Cl₂ (5 mL) was added and the mixture mas stirred at 0° C. for 5 min.The reaction was then warmed to rt and stirred for an additional 15 min.The consumption of the starting material was monitored by TLC(AcOEt/n-hexane 4:6). The reaction was then quenched with sat'd aqNaHCO₃ solution (20 mL). The aqueous layer was extracted with Et₂O (3×20mL). The combined organic layers were washed with brine (30 mL), driedover MgSO₄, gravity filtered, and concentrated under reduced pressure.The crude product was purified by silica gel flash columnchromatography, eluting with AcOEt/n-hexane 3:7, to provide 0.031 g ofthe title compound as an orange solid in a 67% yield.

Data for 19

¹H NMR (400 MHz, CDCl₃) δ 10.13 (s, 1H), 8.02 (d, J=8.0 Hz, 2H),7.90-7.69 (m, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.36-7.10 (m, 1H), 6.52 (d,J=1.9 Hz, 1H), 3.38-3.10 (m, 2H), 2.88 (s, 6H), 2.75-2.54 (m, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.6, 192.5, 148.7, 144.5, 135.6, 135.5(2CH), 133.2, 131.3, 130.7 (2CH), 130.6, 129.6 (2CH), 128.8, 124.9,119.2, 105.3, 40.6 (2CH₃), 37.7, 24.7 ppm

IR (thin film) 2918, 2851, 1703, 1616, 1424, 1166 cm⁻¹

Synthesis of7-(dimethylamino)-9-(4-ethynylphenyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one(20)

A flame-dried 25 mL two-necked round-bottomed flask equipped with anitrogen inlet, a septum and a stir bar was charged with compound 19(0.031 g, 0.094 mmol) and methanol (7 mL). To this solution was addedpotassium carbonate (0.064 g, 0.48 mmol) followed by the Bestmann-Ohirareagent (0.054 g, 0.28 mmol) in methanol (5 mL). The reaction wasstirred at rt overnight. The consumption of the starting material wasmonitored by TLC (AcOEt/n-hexane 2:8). The solution was diluted withether (10 mL) and then transferred to a separatory funnel containingsat'd aq NaHCO₃ solution (15 mL). The layers were separated and theorganic layer was dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel flash column chromatography, eluting with AcOEt/n-hexane 2:8,to provide 0.018 g of the title compound as an orange solid in a 59%yield.

Data for 20

¹H NMR (400 MHz, CDCl₃) δ 7.77-7.73 (m, 2H), 7.63 (d, J=8.0 Hz, 2H),7.37-7.14 (m, 3H), 6.61 (s, 1H), 3.341-3.18 (m, 2H), 3.14 (s, 1H), 2.89(s, 6H), 2.76-2.61 (m, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.5, 148.6, 144.5, 138.2, 136.4, 133.5,132.0 (2CH), 131.2, 130.6, 129.9 (2CH), 128.6, 124.5, 121.2, 119.2,105.8, 84.3, 77.3, 40.7 (2CH₃), 37.7, 24.7 ppm

IR (thin film) 3294, 2919, 2850, 1702, 1602, 1507, 1129 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₂₃H₂₀NO: 326.1545. found: 326.1555.

Literature Preparations

The preparation of N-tert-butoxycarbonyl-L-β-azidoalanine methyl ester(S20) followed the procedure reported by Lee Bioorg. Med. Chem. 2010,18, 7338-7347.

Synthesis of methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)propanoate(21)

A flame-dried 25 mL two-necked round-bottomed flask equipped with aseptum and a stir bar was charged with compound 20 (0.018 g, 0.055 mmol)in CH₂Cl₂ (0.5 mL). N-tert-Butoxycarbonyl-L-β-azidoalanine methyl ester(0.014 g, 0.055 mmol) in t-BuOH/H₂O 1.5:1 (1.2 mL) was then added,followed by sodium ascorbate (0.0022 g, 0.011 mmol) and CuSO₄ (0.0014 g,0.0055 mmol). The reaction was stirred at rt for 2 h. The consumption ofthe starting material was monitored by TLC (AcOEt/n-hexane 7:3). Thereaction was then quenched with H₂O (15 mL). The aqueous layer wasextracted with Et₂O (3×20 mL). The combined organic layers were washedwith brine (30 mL), dried over MgSO₄, gravity filtered, and concentratedunder reduced pressure. The crude product was purified by silica gelflash column chromatography, eluting with AcOEt/n-hexane 7:3, to provide0.019 g of the title compound as an orange solid in a 61% yield.

Data for 21

¹H NMR (400 MHz, CDCl₃) δ 7.94 (br, 2H), 7.79-7.74 (m, 3H), 7.40 (d,J=7.7 Hz, 2H), 7.28-7.25 (m, 1H), 6.72 (s, 1H), 5.46 (br, s, 1H),4.95-4.77 (m, 3H), 3.83 (s, 3H), 3.25 (br, s, 2H), 2.88 (s, 6H), 2.71(br, s, 2H), 1.47 (s, 9H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.7, 169.7, 155.3, 148.6, 148.2, 144.6,137.4, 136.8, 133.7, 131.3, 130.6, 130.5 (2CH), 129.4, 128.6, 125.6(2CH), 124.3, 121.1, 119.2, 106.1, 80.9, 53.9, 53.3, 51.1, 40.7 (2CH₃),37.8, 28.4 (3CH₃), 24.6 ppm

IR (thin film) 3351, 2926, 1701, 1619, 1508, 1164 cm⁻¹

HRMS (TOF MS ES+) [M+H]⁺ calcd for C₃₂H₃₆N₅O₅: 570.2716. found:570.2729.

Synthesis of4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzylundec-10-enoate (22)

An oven-dried, 25 mL one-necked round-bottomed flask was charged withcompound 15b (0.021 g, 0.060 mmol), DCC (0.014 g, 0.069 mmol), DMAP(0.008 g, 0.069 mmol) and dry CH₂Cl₂ (7 mL). 10-Undecenoic acid (0.012mL, 0.060 mmol) was added and the mixture was stirred at rt overnight.The consumption of the starting material was monitored by TLC(AcOEt/n-hexane 1:9). After filtration over a short pad of celite, thereaction was quenched with sat'd aq NaHCO₃ solution (30 mL). The layerswere separated and the aqueous phase was extracted with Et₂O (3×15 mL).The combined organic layers were washed with brine (2×40 mL), dried overMgSO₄, gravity filtered, and concentrated under reduced pressure. Thereaction residue was purified by silica gel flash chromatography,eluting with AcOEt/n-hexane 1.5:8.5, to provide 0.018 g of the titlecompound as a yellow solid in 60% yield.

Data for 22

¹H NMR (400 MHz, CDCl₃) δ 7.76-7.74 (m, 1H), 7.47 (d, J=7.6 Hz, 2H),7.38-7.21 (m, 3H), 6.67 (s, 1H), 5.85-5.75 (m, 1H), 5.25 (s, 2H),5.00-4.90 (m, 2H), 3.33-3.12 (m, 2H), 2.89 (s, 6H), 2.79-2.59 (m, 2H),2.41 (t, J=7.5 Hz, 2H), 2.04-2.01 (m, 2H), 1.75-1.58 (m, 2H), 1.33 (br,10H) ppm

¹³C NMR (100 MHz, CDCl₃) δ 206.6, 173.9, 148.6, 144.6, 139.3, 137.0,135.2, 133.7, 131.3, 130.7, 130.0 (2CH), 128.6, 127.7 (2CH), 124.3,119.2, 114.3, 106.2, 66.2, 40.7 (2CH₃), 37.8, 34.6, 33.9, 29.5, 29.4,29.3, 29.2, 29.1, 25.2, 24.6 ppm

IR (thin film) 2920, 2850, 1726, 1706, 1616, 1376, 1144 cm⁻¹

HRMS (TOF MS ES+)[M+H]⁺ calcd for C₃₃H₄₀NO₃: 498.3008. found: 498.3011.

Tunable Fluorophores—Synthesis

General Procedure A: Conversion of Bromides to Amides

To a flame-dried two-neck round-bottomed flask equipped with an argoninlet adapter, a septum, and a stir bar was added dimethylacetamide (1.0equiv) in THF (0.3 M). The solution was cooled at −78° C. (bathtemperature) in a dry ice/acetone bath and LDA (1.1 equiv of a 2.0 Msolution in heptane/THF/ethylbenzene) was added dropwise via syringewith stirring, turning the reaction mixture light brown. The reactionmixture was stirred at −78° C. for 1 h and became yellow in color.Cinnamyl bromide (1.3-1.5 equiv) dissolved in minimal THF was added tothe reaction all at once, turning the reaction mixture a deeper yellow.The reaction mixture was warmed to rt slowly over 3 h, and then stirredat rt for 16 h becoming cloudy and orange. The reaction mixture waspoured into brine (15 mL), and the aqueous layer was separated andextracted with Et₂O (3×). The combined organic layers were washed withbrine, dried over magnesium sulfate, gravity filtered, and concentratedunder reduced pressure. The crude product was purified by silica gelflash column chromatography to yield the title compound. ¹H NMRspectroscopy showed traces of DCM and ethyl acetate solvents.

(E)-5-(2-Chlorophenyl)-N,N-dimethylpent-4-enamide

Follows general procedure A: dimethylacetamide (0.40 mL, 4.35 mmol), THF(14 mL), LDA (2.40 mL, 4.79 mmol), and cinnamyl bromide x (1.50 g, 6.52mmol). The crude product was purified by silica gel flash columnchromatography (25 g silica cartridge, 0-80% ethyl acetate/hexanes) toyield product x as a yellow oil (0.750 g, 66%).

Data for x LSK-4-056

¹H NMR (300 MHz, CDCl₃) 7.51 (dd, J=7.5, 1.8 Hz, 1H), 7.33 (dd, J=7.5,1.8 Hz, 1H), 7.17 (dt, J=7.5, 1.8 Hz, 2H), 6.81 (d, J=15.8 Hz, 1H), 6.30(dt, J=15.8, 6.6 Hz, 1H), 3.04 (s, 3H), 2.98 (s, 3H), 2.66-2.49 (m, 4H)ppm

¹³C NMR (100 MHz, CDCl₃) 172.0, 135.5, 132.6 (2C), 132.5, 129.5, 128.1,126.8, 126.7, 32.7, 35.4, 32.9, 28.6 ppm

IR (thin film) 3059, 3038, 2930, 1653, 1591, 1496, 1143, 753, 694 cm⁻¹

LRMS (TOF MSMS ES+ ASAP)m/z (%): 238 (100)

HRMS (TOF MS ES+ ASAP)[M+H]⁺ calcd for C₁₃H₁₇NOCl: 238.0999. found,238.0997.

(E)-5-(3-Chlorophenyl)-N,N-dimethylpent-4-enamide

Follows general procedure A: dimethylacetamide (0.47 mL, 5.02 mmol), THF(16 mL), LDA (2.76 mL, 5.52 mmol), and cinnamyl bromide x (1.50 g, 6.52mmol). The crude product was purified by silica gel flash columnchromatography (25 g silica cartridge, 0-80% ethyl acetate/hexanes) toyield product as a golden oil (0.894 g, 68%).

Data LSK-4-064

¹H NMR (300 MHz, CDCl₃) 7.34 (s, 1H), 7.27-7.15 (m, 3H), 6.39 (d, J=16.0Hz, 1H), 6.26 (dt, J=16.0, 6.0 Hz, 1H), 3.02 (s, 3H), 2.97 (s, 3H),2.58-2.45 (m, 4H) ppm

¹³C NMR (100 MHz, CDCl₃) 172.0, 139.4, 134.4, 131.3, 129.7, 129.3,126.9, 125.9, 124.3, 37.2, 35.4, 32.9, 28.5 ppm

IR (thin film) 3051, 2932, 2902, 1639, 1593, 1142, 752, 735 cm⁻¹

LRMS (TOF MSMS ES+ ASAP)m/z (%): 238 (100)

HRMS (TOF MS ES+ ASAP) [M+H]⁺ calcd for C₁₃H₁₇NOCl: 238.0999. found,238.0995.

General Procedure B: Addition of Alkynes

To a flame-dried two-neck round-bottomed flask equipped with an argoninlet adapter, a septum, and a stir bar was added alkyne (1.3 equiv) inTHF (0.4 M). The solution was cooled at −78° C. (bath temperature) in adry ice/acetone bath, and n-butyllithium (1.2 equiv of a 1.6 M solutionin hexanes) was added dropwise via syringe with stirring. The reactionwas stirred at −78° C. for 1 h, then amide (1.0 equiv) in THF (0.3 M)followed by boron trifluoride diethyl etherate (1.25 equiv) were addeddropwise via syringe. The reaction was stirred at −78° C. for 1 h, andboron trifluoride diethyl etherate (1.25 equiv) and acetic acid (1.25equiv) were added. The reaction was warmed to −20° C. and quenched withsat'd aq ammonium chloride solution. The aqueous layer was separated andextracted with Et₂O (2×). The combined organic layers were washed withbrine, dried over magnesium sulfate, gravity filtered, and concentratedunder reduced pressure. The crude product was purified by silica gelflash column chromatography to yield the title compound.

(E)-7-(2-Chlorophenyl)-1-phenylhept-6-en-1-yn-3-one

Follows general procedure B: phenylacetylene (90 μL, 0.82 mmol), THF (2mL), n-butyllithium (0.43 mL, 0.69 mmol), amide (0.150 g, 0.63 mmol),THF (2 mL), boron trifluoride diethyl etherate (99 μL, 0.79 mmol),acetic acid (45 μL, 0.79 mmol). The crude product was purified by silicagel flash column chromatography (12 g silica cartridge, 0-10% ethylacetate/hexanes) to yield the title compound as a light yellow oil(0.148 g, 80%).

Data LSK-4-062

¹H NMR (300 MHz, CDCl₃) 7.61-7.58 (m, 2H), 7.52-7.45 (m, 2H), 7.41 (d,J=7.7 Hz, 2H), 7.38-7.32 (m, 1H), 7.18 (dp, J=7.7, 1.9 Hz, 2H), 6.86 (d,J=15.6 Hz, 1H), 6.24 (dt, J=15.6, 6.9 Hz, 1H), 2.90 (t, J=7.2 Hz, 2H),2.71 (q, J=7.2 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 186.9, 135.4, 133.1 (2C), 132.7, 131.1, 130.8,129.6, 128.7 (2C), 128.2, 127.5, 126.8, 126.7, 119.9, 91.3, 87.8, 44.9,27.6 ppm

IR (thin film) 3062, 2899, 2848, 2200, 1667, 1591, 1489, 755 cm⁻¹

LRMS (TOF MSMS ES+ ASAP)m/z (%): 294 (73), 293 (98), 259 (100)

HRMS (TOF MS ES+ ASAP) [M] calcd for C₁₉H₁₅OCl: 294.0811. found, 294.08.

(E)-7-(3-Chlorophenyl)-1-phenylhept-6-en-1-yn-3-one

Follows general procedure B: phenylacetylene (0.12 mL, 1.09 mmol), THF(3 mL), n-butyllithium (0.63 mL, 1.01 mmol), amide (0.200 g, 0.84 mmol),THF (3 mL), boron trifluoride diethyl etherate (0.13 mL, 1.05 mmol),acetic acid (60 μL, 1.05 mmol). The crude product was purified by silicagel flash column chromatography (3 cm column, 10% ethyl acetate/hexanes)to yield the title compound as a yellow oil (0.239 g, 96%).

Data LSK-4-207 (NMR 4-070)

¹H NMR (300 MHz, CDCl₃) 7.61-7.57 (m, 2H), 7.50-7.37 (m, 3H), 7.33 (s,1H), 7.23-7.16 (m, 3H), 6.42 (d, J=16.0 Hz, 1H), 6.26 (dt, J=16.0, 6.6Hz, 1H), 2.87 (t, J=7.2 Hz, 2H), 2.66 (q, J=7.2 Hz, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 186.7, 139.2, 134.5, 133.1 (2C), 130.8, 130.0,129.8, 129.7, 128.7 (2C), 127.1, 126.0, 124.3, 119.9, 91.2, 87.8, 44.8,27.3 ppm

IR (thin film) 3061, 3023, 2923, 2851, 2202, 1668, 1593, 1489, 758, 688cm⁻¹

LRMS (TOF MSMS ES+ ASAP)m/z (%): 294 (100), 293 (50), 259 (20)

HRMS (TOF MS ES+ ASAP) [M+H]⁺ calcd for C₁₉H₁₆OCl: 294.0890. found,294.0895.

(E)-7-(2-Chlorophenyl)-1-(trimethylsilyl)hept-6-en-1-yn-3-one

Follows general procedure B: trimethylsilylacetylene (0.28 mL, 1.99mmol), THF (5.4 mL), n-butyllithium (1.15 mL, 1.84 mmol), amide (0.400g, 1.53 mmol), THF (5.4 mL), boron trifluoride diethyl etherate (0.24mL, 1.91 mmol), acetic acid (0.11 mL, 1.91 mmol). The crude product waspurified by silica gel flash column chromatography (12 g silicacartridge, 0-10% ethyl acetate/hexanes) to yield the title compound as alight yellow oil (0.268 g, 60%).

Data LSK-4-063

¹H NMR (300 MHz, CDCl₃) 7.48 (dd, J=7.5, 1.8 Hz, 1H), 7.34 (dd, J=7.5,1.8 Hz, 1H), 7.18 (dp, J=7.5, 1.8 Hz, 2H), 6.82 (d, J=15.8 Hz, 1H), 6.19(dt, J=15.8, 6.8 Hz, 1H), 2.79 (t, J=7.2 Hz, 2H), 2.63 (q, J=7.2 Hz,2H), 0.26 (s, 9H) ppm

¹³C NMR (100 MHz, CDCl₃) 187.4, 136.1, 133.4, 131.7, 130.4, 129.0,128.2, 127.6, 127.5, 102.6, 99.2, 45.4, 28.2, 0.0 (3C) ppm

IR (thin film) 3062, 2961, 2901, 2150, 1677, 1591, 1469, 1252, 847, 751cm⁻¹

LRMS (TOF MS ES+ ASAP)m/z (%): 293 (30), 291 (100), 290 (32), 276 (25),275 (79), 255 (20), 239 (15)

HRMS (TOF MS ES+ ASAP) [M+H]⁺ calcd for C₁₆H₂₀OSiCl: 291.0972. found,291.0961.

(E)-7-(3-Chlorophenyl)-1-(trimethylsilyl)hept-6-en-1-yn-3-one

Follows general procedure B: trimethylsilylacetylene (70 μL, 0.49 mmol),THF (1.4 mL), n-butyllithium (0.29 mL, 0.46 mmol), amide (0.100 g, 0.42mmol), THF (1.4 mL), boron trifluoride diethyl etherate (60 μL, 0.48mmol), acetic acid (27 μL, 0.48 mmol). The crude product was purified bysilica gel flash column chromatography (12 g silica cartridge, 0-10%ethyl acetate/hexanes) to yield the title compound as a light yellow oil(0.076 g, 68%).

Data LSK-4-085

¹H NMR (300 MHz, CDCl₃) 7.32 (s, 1H), 7.20-7.16 (m, 3H), 6.38 (d, J=16.0Hz, 1H), 6.21 (dt, J=16.0, 6.7 Hz, 1H), 2.78 (t, J=6.6 Hz, 2H), 2.58 (q,J=6.6 Hz, 2H), 0.26 (s, 9H) ppm

¹³C NMR (100 MHz, CDCl₃) 186.8, 139.1, 134.4, 129.9, 129.7, 129.7,127.1, 126.0, 124.3, 101.8, 98.4, 44.6, 27.1, 0.0 (3C) ppm

IR (thin film) 3055, 3025, 2960, 2901, 2150, 1677, 1252, 846, 762 cm⁻¹

LRMS (TOF MS ES+ ASAP)m/z (%): 293 (29), 291 (100), 290 (10), 276 (20),275 (56), 255 (25), 239 (5)

HRMS (TOF MS ES+ ASAP) [M+H]⁺ calcd for C₁₆H₂₀OSiCl: 291.0972. found,291.0981.

Dehydrogenative Dehydro-Diels-Alder Reaction

General Procedure C: Dehydrogenative Dehydro-Diels-Alder Reaction

To a 2-5 mL microwave irradiation vial was added styrene-yne in DCB(0.06 M). The solution was irradiated at 225° C. until complete by TLC.The reaction mixture was purified by silica gel flash columnchromatography to yield the title compound.

5-Chloro-9-phenyl-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one

Follows general procedure C: styrene-yne (0.110 g, 0.37 mmol) and DCB (5mL). The solution was irradiated at 225° C. for 40 min turning thereaction mixture amber. The reaction mixture was purified directly bysilica gel flash column chromatography (2.5 cm column, 0-10% ethylacetate/hexanes) to yield the title compound as a yellow solid (0.105 g,96%).

Data LSK-4-069

¹H NMR (300 MHz, CDCl₃) 8.42 (s, 1H), 7.68 (d, J=7.2 Hz, 1H), 7.63 (d,J=8.7 Hz, 1H), 7.53-7.50 (m, 3H), 7.32-7.26 (m, 3H), 3.41-3.36 (m, 2H),2.79-2.74 (m, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 205.7, 149.2, 140.2, 135.7, 134.0, 133.5,131.7, 131.4, 129.7 (2C), 128.4, 128.0 (2C), 127.9, 127.8, 125.5, 121.3,37.5, 25.1 ppm

IR (thin film) 3060, 3025, 2958, 2924, 1710, 1595, 1483 cm⁻¹

LRMS (TOF MSMS ES+ ASAP)m/z (%): 293 (100), 251 (63), 230 (5), 216 (10),215 (12)

HRMS (TOF MS ES+ ASAP) [M+H]⁺ calcd for C₁₉H₁₄OCl: 293.0733. found,293.0728.

6-Chloro-9-phenyl-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one and8-chloro-9-phenyl-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one

Follows general procedure C: styrene-yne (0.110 g, 0.37 mmol) and DCB (5mL). The solution was irradiated at 225° C. for 40 min turning thereaction mixture amber. The reaction mixture was concentrated under highvacuum, and the crude products were purified by silica gel flash columnchromatography (25 g silica cartridge, 0-10% ethyl acetate/hexanes) toyield the title compounds as beige solids (combined yield of 0.084 g,77%).

Data for 6-chloro compound LSK-4-077-1

Yield 0.036 g, 33% yield

¹H NMR (400 MHz, C₆D₆) 7.60 (s, 1H), 7.57 (d, J=9.2 Hz, 1H), 7.33-7.29(m, 2H), 7.27-7.24 (m, 3H), 7.11 (s, 1H), 7.03 (d, J=9.2 Hz, 1H),2.54-2.50 (m, 2H), 2.20-2.16 (m, 2H) ppm

¹³C NMR (100 MHz, C₆D₆) 203.5, 149.3, 140.0, 137.5, 136.2, 134.4, 131.6,130.8 (2C), 130.5 (2C), 130.2, 126.9 (2C), 126.5 (2C), 123.8, 37.2, 24.6ppm

LRMS (TOF MSMS ES+ ASAP)m/z (%): 292 (48), 291 (100), 257 (5), 215 (2)

HRMS (TOF MS ES+ ASAP) [M+H]⁺ calcd for C₁₉H₁₄OCl: 293.0733. found,293.0723.

Data for 8-chloro compound LSK-4-077-2

Yield 0.048 g, 44% yield

¹H NMR (300 MHz, CDCl₃) 7.94 (s, 1H), 7.82 (dd, J=7.8, 1.9 Hz, 1H),7.50-7.37 (m, 5H), 7.26-7.23 (m, 2H), 3.30-3.25 (m, 2H), 2.72-2.68 (m,2H) ppm

¹³C NMR (100 MHz, CDCl₃) 205.2, 148.1, 139.8, 138.9, 138.0, 134.2,133.0, 130.0, 129.3 (2C), 128.1, 127.9, 127.8, 127.3, 127.2 (2C), 125.9,37.5, 24.1 ppm

IR (thin film) 3056, 3028, 2928, 2864, 1708, 1612, 1497 cm⁻¹

LRMS (TOF MSMS ES+ ASAP)m/z (%): 292 (100), 291 (12), 257 (44)

HRMS (TOF MS ES+ ASAP) [M+H]⁺ calcd for C₁₉H₁₄OCl: 293.0733. found,293.0727.

5-Chloro-9-(trimethylsilyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one

Follows general procedure C: styrene-yne (0.052 g, 0.18 mmol) and DCB (3mL). The solution was irradiated at 225° C. for 90 min turning thereaction mixture amber. The reaction mixture was purified directly bysilica gel flash column chromatography (2.5 cm column, 0-5% ethylacetate/hexanes) to yield the title compound as an off-white solid(0.047 g, 91%).

Data LSK-4-097

¹H NMR (400 MHz, CDCl₃) 8.42-8.40 (m, 2H), 7.65 (d, J=7.8 Hz, 1H), 7.37(t, J=7.8 Hz, 1H), 3.37-3.34 (m, 2H), 2.81-2.78 (m, 2H), 0.55 (s, 9H)ppm

¹³C NMR (100 MHz, CDCl₃) 207.9, 148.7, 143.3, 142.4, 138.5, 133.3,132.0, 130.1, 127.9, 124.7, 123.1, 36.9, 25.5, 3.1 (3C) ppm

IR (thin film) 3089, 2966, 2939, 2889, 1714, 1591, 1487, 1249, 1240 cm⁻¹

LRMS (TOF MS ES+ ASAP)m/z (%): 289 (22), 275 (28), 273 (100),

HRMS (TOF MS ES+ ASAP) [M+H]⁺ calcd for C₁₆H₁₈OSiCl: 289.0815. found,289.0791.

6-Chloro-9-(trimethylsilyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-oneand8-chloro-9-(trimethylsilyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one

Follows general procedure C: styrene-yne (0.073 g, 0.25 mmol) and DCB(4.2 mL). The solution was irradiated at 225° C. for 90 min turning thereaction mixture brown. The reaction mixture was concentrated under highvacuum, and the crude products were purified by silica gel flash columnchromatography (12 g silica cartridge, 0-10% ethyl acetate/hexanes) toyield the title compounds as white solids (combined yield of 0.057 g,79%).

Data for 6-chloro compound LSK-4-083-1

Yield 0.033 g, 46% yield

¹H NMR (300 MHz, CDCl₃) 8.42 (d, J=9.2 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H),7.79 (s, 1H), 7.40 (dd, J=9.2, 2.2 Hz, 1H), 3.32-3.28 (m, 2H), 2.80-2.75(m, 2H), 0.54 (s, 9H) ppm

¹³C NMR (100 MHz, CDCl₃) 207.6, 148.6, 142.8, 141.8, 136.7, 135.5,133.5, 132.2, 126.9, 126.0, 125.6, 36.8, 25.2, 2.94 (3C) ppm

IR (thin film) 2966, 2943, 2884, 1706, 1607, 1485 cm⁻¹

LRMS (TOF MSMS ES+ ASAP)m/z (%): 273 (100), 243 (18), 229 (25), 199 (48)

HRMS (TOF MS ES+ ASAP) [M-CH₃] calcd for C₁₅H₁₄OSiCl: 273.0502. found,273.0498.

Data for 8-chloro compound LSK-4-083-2

Yield 0.024 g, 33% yield

¹H NMR (300 MHz, CDCl₃) 7.78 (s, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.55 (d,J=7.2 Hz, 1H), 7.42 (t, J=8.1 Hz, 1H), 3.31-3.26 (m, 2H), 2.81-2.76 (m,2H), 0.44 (s, 9H) ppm

¹³C NMR (100 MHz, CDCl₃) 207.9, 146.8, 145.3, 144.1, 137.5, 136.8,135.3, 127.4, 127.3, 127.3, 126.4, 37.0, 25.2, 2.96 (3C) ppm

IR (thin film) 2953, 2941, 2913, 1707, 1601, 1479 cm⁻¹

LRMS (TOF MSMS ES+ ASAP)m/z (%): 273 (51), 257 (23), 231 (100), 199 (31)

HRMS (TOF MS ES+ ASAP) [M-Me] calcd for C₁₅H₁₄OSiCl: 273.0502. found,273.0476.

General Procedure D: Desilylation of Naphthalenes

To a two-neck round-bottomed flask equipped with an argon inlet adapter,a septa, and a stir bar was added naphthalene (1.0 equiv) in THF(0.06-0.08 M). TBAF (2.0-3.0 equiv of a 1.0 M solution in THF) was addeddropwise with stirring turning the reaction mixture purple then brown incolor. The reaction mixture was stirred at rt for 30 min and quenchedwith sat'd aq ammonium chloride. The aqueous layer was separated andextracted with ethyl acetate (3×). The combined organic layers werewashed with brine, dried over magnesium sulfate, gravity filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel flash column chromatography to yield the title compound.

5-Chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one

Follows general procedure D: naphthalene (0.046 g, 0.16 mmol), THF (2mL), and TBAF (0.35 mL, 0.35 mmol). The crude product was purified bysilica gel flash column chromatography (4 g silica cartridge, 0-10%ethyl acetate/hexanes) to yield a light yellow solid (18 mg, 51%).

Data LSK-4-099

¹H NMR (400 MHz, CDCl₃) 8.31 (s, 1H), 8.28 (s, 1H), 7.88 (d, J=8.4 Hz,1H), 7.66 (d, J=7.5 Hz, 1H), 7.39 (t, J=7.5 Hz, 1H), 3.37-3.34 (m, 2H),2.83-2.80 (m, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 206.9, 149.1, 135.3, 134.3, 133.5, 131.7,129.6, 128.7, 125.9, 124.6, 121.8, 36.9, 25.6 ppm

IR (thin film) 3056, 2958, 2921, 2839, 1710, 1625, 1593, 1497 cm⁻¹

LRMS (TOF MSMS ES+ ASAP) m/z (%): 216 (100), 188 (3), 181 (2)

HRMS (TOF MS ES+ ASAP) [M] calcd for C₁₃H₉OCl: 216.0342. found,216.0340.

6-Chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one

Follows general procedure D: naphthalene (0.058 g, 0.20 mmol), THF (3.3mL), and TBAF (0.62 mL, 0.62 mmol). The crude product was purified bysilica gel flash column chromatography (2.5 cm column, 5-10% ethylacetate/hexanes) to yield a light brown solid (21 mg, 50%).

Data LSK-4-178

¹H NMR (300 MHz, CDCl₃) 8.29 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.85 (s,1H), 7.81 (s, 1H), 7.44 (dd, J=8.8, 2.0 Hz, 1H), 3.35-3.31 (m, 2H),2.83-2.79 (m, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 206.8, 149.1, 137.6, 135.0, 134.5, 131.8,130.5, 127.2, 126.4, 124.3, 124.0, 36.9, 25.4 ppm

IR (thin film) 3068, 3019, 2953, 2922, 2847, 1710, 1628, 1492 cm⁻¹

LRMS (TOF MSMS ES+ ASAP)m/z (%): 217 (100), 199 (7), 188 (8), 175 (15)

HRMS (TOF MS ES+ ASAP) [M+H]⁺ calcd for C₁₃H₁₀OCl: 217.0420. found,217.0404.

8-Chloro-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one

Follows general procedure D: naphthalene (0.035 g, 0.12 mmol), THF (2mL), and TBAF (0.24 mL, 0.24 mmol). The crude product was purified bysilica gel flash column chromatography (1.5 cm column, 10% ethylacetate/hexanes) to yield a light brown solid (17 mg, 65%).

Data LSK-4-180

¹H NMR (300 MHz, CDCl₃) 8.78 (s, 1H), 7.93 (s, 1H), 7.79 (dd, J=8.1 Hz,1H), 7.59 (d, J=6.9 Hz, 1H), 7.49 (t, J=8.1 Hz, 1H), 3.37-3.33 (m, 2H),2.86-2.82 (m, 2H), ppm

¹³C NMR (100 MHz, CDCl₃) 206.9, 148.7, 138.1, 135.5, 134.4, 130.0,128.3, 126.9, 126.3, 125.3, 121.2, 36.9, 25.2 ppm

IR (thin film) 2956, 2925, 2851, 1709, 1626, 1596, 1496 cm⁻¹

LRMS (TOF MSMS ES+ ASAP) m/z (%): 217 (100), 216 (12), 199 (5), 188(30), 175 (13)

HRMS (TOF MS ES+ ASAP) [M+H]⁺ calcd for C₁₃H₁₀OCl: 217.0420. found,217.0412.

Buchwald-Hartwig Cross-Coupling Reaction

General Procedure E: Buchwald-Hartwig Cross-coupling Reactions EmployingLHMDS

To an oven-dried 0.5-2 mL microwave irradiation vial equipped with astir bar was added Ruphos palladacycle (0.025 equiv). The microwaveirradiation vial was capped and then evacuated and refilled with argon(3×) through a small gauge needle piercing the vial cap. Once evacuationof air from the vial was complete, the needle was removed. LHMDS (2.0equiv of a 1.0 M solution in THF) was added all at once with stirring,turning the reaction mixture red. Naphthalene (1.0 equiv) in THF(0.25-0.50 M) was added all at once via syringe turning the reactionmixture brown in color. Finally, dimethylamine (1.5 equiv of a 2.0 Msolution in THF) was added via syringe. The reaction mixture was heatedat 85° C. in an oil bath until complete by TLC. Once complete, thereaction mixture was cooled to rt, diluted with sat'd aq ammoniumchloride solution, and extracted with ethyl acetate (3×). The combinedorganic layers were dried over MgSO₄, gravity filtered, and concentratedunder reduced pressure. The crude product was purified by silica gelflash column chromatography to yield the title compound.

General Procedure F: Buchwald-Hartwig Cross-coupling Reactions EmployingCs₂CO₃

To an oven-dried 0.5-2 mL microwave irradiation vial equipped with astir bar was added Ruphos palladacycle (0.025 equiv), Cs₂CO₃ (2.0equiv), and naphthalene (1.0 equiv). The microwave irradiation vial wascapped and then evacuated and refilled with argon (3×) through a smallgauge needle piercing the vial cap. Once evacuation of air from the vialwas complete, the needle was removed. THF (0.25-0.50 M) was added all atonce via syringe, followed by dimethylamine (1.5-3.0 equiv of a 2.0 Msolution in THF). The reaction mixture was heated at 85° C. in an oilbath until complete by TLC. Once complete, the reaction mixture wascooled to rt, diluted with sat'd aq ammonium chloride solution, andextracted with ethyl acetate (3×). The combined organic layers weredried over MgSO₄, gravity filtered, and concentrated under reducedpressure. The crude product was purified by silica gel flash columnchromatography to yield the title compound.

5-(Dimethylamino)-9-phenyl-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one

Follows general procedure E: Ruphos palladacycle (4 mg, 0.0053 mmol),LHMDS (0.42 mL, 0.42 mmol), naphthalene (0.060 g, 0.21 mmol), THF (0.8mL), and dimethylamine (0.16 mL, 0.32 mmol). The reaction mixture washeated at 85° C. for 1 h, turning the reaction mixture black. The crudeproduct was purified by silica gel flash column chromatography (12 gsilica cartridge, 0-15% ethyl acetate/hexanes) to yield the titlecompound as a dark yellow solid (0.030 g, 48%).

Data LSK-4-078

¹H NMR (300 MHz, CDCl₃) 8.37 (s, 1H), 7.51-7.46 (m, 3H), 7.35 (d, J=8.4Hz, 1H), 7.31-7.27 (m, 3H), 7.18 (dd, J=7.2, 1.2 Hz, 1H), 3.36-3.32 (m,2H), 2.93 (s, 6H), 2.75-2.71 (m, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 206.2, 150.6, 147.6, 140.1, 136.8, 133.4,132.7, 130.8, 129.8 (2C), 127.9 (2C), 127.6, 125.7, 123.3, 120.8, 116.5,45.4 (2C), 37.6, 25.1 ppm

IR (thin film) 3062, 2991, 2955, 2829, 2786, 1717, 1609, 1591, 1489 cm⁻¹

LRMS (TOF MSMS ES+ ESI) m/z (%): 302 (30), 287 (100)

HRMS (TOF MS ES+ ESI) [M+H]⁺ calcd for C₂₁H₂₀NO: 302.1545. found,302.1559.

6-(Dimethylamino)-9-phenyl-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one

Follows general procedure E: Ruphos palladacycle (1.5 mg, 0.0020 mmol),LHMDS (0.14 mL, 0.14 mmol), naphthalene (0.019 g, 0.065 mmol), THF (0.13mL), and dimethylamine (50 μL, 0.10 mmol). The reaction mixture washeated at 85° C. for 1.5 h, turning reaction mixture brown. The crudeproduct was purified by silica gel flash column chromatography (1.5 cmcolumn, 5% ethyl acetate/hexanes) to yield the title compound as ayellow solid (3 mg, 15%).

Data LSK-4-106

¹H NMR (300 MHz, CDCl₃) 7.63 (s, 1H), 7.53 (d, J=9.3 Hz, 1H), 7.50-7.45(m, 3H), 7.30 (d, J=6.4 Hz, 2H), 7.01 (d, J=9.3 Hz, 1H), 6.85 (s, 1H),3.22 (t, J=6.6 Hz, 2H), 3.10 (s, 6H), 2.67 (t, J=6.6 Hz, 2H) ppm

¹³C NMR (175 MHz, CDCl₃) 205.5, 149.8, 149.1 140.0, 139.1, 136.7, 129.7(2C), 129.5, 127.7 (2C), 127.4 (2C), 124.8, 121.6, 115.9, 104.5, 40.3(2C), 37.4, 24.7 ppm

LRMS (TOF MSMS ES+ ASAP) m/z (%): 301 (100), 300 (28)

HRMS (TOF MS ES+ ASAP) [M] calcd for C₂₁H₁₉NO: 301.1467. found,301.1469.

5-(Dimethylamino)-9-(trimethylsilyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one

Follows general procedure F: Ruphos palladacycle (1.5 mg, 0.0020 mmol),Cs₂CO₃ (0.045 g, 0.14 mmol), naphthalene (0.020 g, 0.069 mmol), THF(0.25 mL), and dimethylamine (0.11 mL, 0.21 mmol). The reaction mixturewas heated at 85° C. for 3.5 h, turning the reaction mixture from cloudyorange to dark brown. The crude product was purified by silica gel flashcolumn chromatography (1.25 cm, 3% ethyl acetate/hexanes) to yield thetitle compound as a yellow solid (14 mg, 68%).

Data LSK-5-115

¹H NMR (700 MHz, CDCl₃) 8.37 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.36 (t,J=7.7 Hz, 1H), 7.15 (d, J=7.7 Hz, 1H), 3.32-3.30 (m, 2H), 2.89 (s, 6H),2.77-2.75 (m, 2H), 0.53 (s, 9H) ppm

¹³C NMR (175 MHz, CDCl₃) 208.2, 150.8, 147.2, 142.7, 141.4, 138.7,131.9, 125.9, 124.7, 122.7, 115.8, 45.4 (2C), 37.1, 29.7 (grease), 25.6,3.03 (3C) ppm

LRMS (TOF MSMS ES+ ESI) m/z (%): 298 (20), 283 (11), 268 (100), 209 (7)

HRMS (TOF MS ES+ ESI) [M+H]⁺ calcd for C₁₈H₂₄NOSi: 298.1627. found,298.1616.

6-(Dimethylamino)-9-(trimethylsilyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one

Follows general procedure F: Ruphos palladacycle (2 mg, 0.0027 mmol),Cs₂CO₃ (0.056 g, 0.17 mmol), naphthalene (0.025 g, 0.087 mmol), THF(0.40 mL), and dimethylamine (0.13 mL, 0.26 mmol). The reaction mixturewas heated at 85° C. for 5 h, turning the reaction mixture from red todark brown over time. The crude product was purified by silica gel flashcolumn chromatography (1.5 cm, 5% ethyl acetate/hexanes) to yield thetitle compound as a yellow solid (20 mg, 78%).

Data LSK-4-201

¹H NMR (300 MHz, CDCl₃) 8.32 (d, J=9.3 Hz, 1H), 7.61 (s, 1H), 7.11 (dd,J=9.3, 2.8 Hz, 1H), 6.80 (d, J=2.8 Hz, 1H), 3.23-3.21 (m, 2H), 3.10 (s,6H), 2.72-2.68 (m, 2H), 0.52 (s, 9H) ppm

¹³C NMR (100 MHz, CDCl₃) 207.4, 149.1, 148.8, 142.2, 138.5, 137.9,131.8, 130.6, 123.8, 115.3, 105.2, 40.3 (2C), 36.8, 25.2, 3.1 (3C) ppm

IR (thin film) 2956, 2923, 2887, 2851, 1696, 1616, 1507 cm⁻¹

LRMS (TOF MSMS ES+ ESI) m/z (%): 297 (100), 281 (5)

HRMS (TOF MS ES+ ESI) [M+H]⁺ calcd for C₁₈H₂₄NOSi: 298.1627. found,298.1630.

5-(Dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one

Follows general procedure E: Ruphos palladacycle (1.5 mg, 0.0020 mmol),LHMDS (0.14 mL, 0.14 mmol), naphthalene (0.016 g, 0.072 mmol), THF (0.20mL), and dimethylamine (54 μL, 0.11 mmol). The reaction mixture washeated at 85° C. for 1.5 h, turning the reaction mixture dark brown overtime. The crude product was purified by silica gel flash columnchromatography (1.5 cm, 5% ethyl acetate/hexanes) to yield the titlecompound as a yellow solid (8 mg, 50%).

Data LSK-4-107

¹H NMR (300 MHz, CDCl₃) 8.32-8.29 (m, 2H), 7.66 (d, J=7.8 Hz, 1H), 7.41(t, J=7.8 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 3.37-3.33 (m, 2H), 2.91 (s,6H), 2.83-2.78 (m, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 207.6, 150.7, 147.6, 134.5, 133.7, 133.0,126.0, 125.3, 124.7, 121.3, 116.8, 45.2 (2C), 37.1, 25.7 ppm

IR (thin film) 3056, 2925, 2852, 2823, 2786, 1712, 1626, 1601, 1503 cm⁻¹

LRMS (TOF MSMS ES+ ASAP) m/z (%): 225 (100), 224 (35), 196 (3), 182 (10)

HRMS (TOF MS ES+ ASAP) [M] calcd for C₁₅H₁₅NO: 225.1154. found,225.1147.

6-(Dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one

Follows general procedure E: Ruphos palladacycle (2 mg, 0.0027 mmol),LHMDS (0.18 mL, 0.18 mmol), naphthalene (0.019 g, 0.088 mmol), THF (0.30mL), and dimethylamine (0.13 mL, 0.26 mmol). The reaction mixture washeated at 85° C. for 1 h, turning the reaction mixture brown over time.The crude product was purified by silica gel flash column chromatography(1.5 cm, 10% ethyl acetate/hexanes) to yield the title compound as alight brown solid (5 mg, 25%).

Data LSK-4-184

¹H NMR (300 MHz, CDCl₃) 8.16 (s, 1H), 7.81 (d, J=9.1 Hz, 1H), 7.60 (s,1H), 7.14 (dd, J=9.1, 2.3 Hz, 1H), 6.82 (d, J=2.3 Hz, 1H), 3.26-3.21 (m,2H), 3.12 (s, 6H), 2.77-2.72 (m, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 207.0, 150.2, 149.0, 139.5, 131.5, 131.2,125.4, 124.4, 121.8, 116.3, 104.6, 40.4 (2C), 36.9, 25.3 ppm

IR (thin film) 2959, 2918, 2851, 1693, 1614, 1512 cm⁻¹

LRMS (TOF MSMS ES+ ASAP) m/z (%): 225 (31), 224 (100), 209 (32), 196(5), 184 (17)

HRMS (TOF MS ES+ ASAP) [M+H]⁺ calcd for C₁₅H₁₆NO: 226.1232. found,226.1189.

8-(Dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one

Follows general procedure E: Ruphos palladacycle (1.5 mg, 0.0020 mmol),LHMDS (0.15 mL, 0.15 mmol), naphthalene (0.016 g, 0.074 mmol), THF (0.30mL), and dimethylamine (0.11 mL, 0.22 mmol). The reaction mixture washeated at 85° C. for 2.5 h, turning the reaction mixture dark brown overtime. The crude product was purified by silica gel flash columnchromatography (1.5 cm, 5% ethyl acetate/hexanes) to yield the titlecompound as a yellow solid (13 mg, 77%).

Data LSK-4-186

¹H NMR (300 MHz, CDCl₃) 8.74 (s, 1H), 7.85 (s, 1H), 7.49-7.47 (m, 2H),7.03 (dd, J=5.8, 2.6 Hz, 1H), 3.32-3.29 (m, 2H), 2.91 (s, 6H), 2.82-2.79(m, 2H) ppm

¹³C NMR (100 MHz, CDCl₃) 207.5, 153.4, 147.9, 138.8, 133.9, 128.7,128.1, 125.1, 122.2, 121.4, 113.9, 45.3 (2C), 37.0, 25.2 ppm

IR (thin film) 3053, 2936, 2867, 2837, 1710, 1623, 1595, 1575, 1501 cm⁻¹

LRMS (TOF MSMS ES+ ASAP) m/z (%): 226 (16), 225 (67), 211 (100)

HRMS (TOF MS ES+ ASAP) [M+H]⁺ calcd for C₁₅H₁₆NO: 226.1232. found,226.1193.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about”. Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specifications and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent disclosure. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of the invention areapproximations, the numerical values set forth in the specific examplesare reported as precisely as possible. Any numerical value, however,inherently contains certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.

All numerical ranges stated herein include all sub-ranges subsumedtherein. For example, a range of “1 to 10” is intended to include allsub-ranges between and including the recited minimum value of 1 and therecited maximum value of 10. Any maximum numerical limitation recitedherein is intended to include all lower numerical limitations. Anyminimum numerical limitation recited herein is intended to include allhigher numerical limitations.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, for any reference made to patents and printed publicationsthroughout this specification, each of the cited references and printedpublications are individually incorporated herein by reference in theirentirety.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

We claim:
 1. A functionalized naphthalene fluorophore having astructure: a)1-(5-(dimethylamino)-2′,2′-dimethyl-1,3-dihydrospiro[cyclopenta[b]naphthalene-2,5′-[1,3]dioxan]-9-yl)ethanone; b)1-(5-(dimethylamino)-2′,2′-dimethyl-1,3-dihydrospiro[cyclopenta[b]naphthalene-2,5′-[1,3]dioxan]-9-yl)-2,2-dimethylpropan-1-one; c)1-(2,2-bis(((tert-butyldimethylsilyl)oxy)methyl)-8-(dimethylamino)-2,3-dihydro-1H-cyclo-penta[b]naphthalen-4-yl)ethanone;d) 1-(2′,2′-dimethyl-5-(pyrrolidin-1-yl)-1,3-dihydrospiro[cyclopenta[b]naphthalene-2,5′-[1,3]dioxan]-9-yl)ethanone; e)1-(8-(dimethylamino)-2,2-bis(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone;f)1-(8-(dimethylamino)-2,2-bis(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)-2,2-dimethylpropan-1-one;g)1-(2,2-bis(hydroxymethyl)-8-(pyrrolidin-1-yl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)ethanone;h)(8-(dimethylamino)-4-pivaloyl-2,3-dihydro-1H-cyclopenta[b]naphthalene-2,2-diyl)bis(methylene)bis(undec-10-enoate); i)6-((tert-butyldimethylsilyl)oxy)-1-(8-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)hexan-1-one;j)1-(8-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)-6-hydroxyhexan-1-one;k)9-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)-7-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;l)7-(dimethylamino)-9-(4-(2-hydroxyethoxy)phenyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;m)9-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-7-(dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;n)7-(dimethylamino)-9-(4-(hydroxymethyl)phenyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;o)2-(4-(6-dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)dione; p)1-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzyl)-1H-pyrrole-2,5-dione;q) ethyl2-((tert-butoxycarbonyl)amino)-3-41-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzyl)-2,5-dioxopyrrolidin-3-yl)thio)propanoate;r)4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzaldehyde;s)7-(dimethylamino)-9-(4-ethynylphenyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;t) methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)propanoate;u)4-(6-(dimethylamino)-3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-4-yl)benzylundec-10-enoate;v)5-(Dimethylamino)-9-phenyl-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;w)6-(Dimethylamino)-9-phenyl-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;x)5-(Dimethylamino)-9-(trimethylsilyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;y)6-(Dimethylamino)-9-(trimethylsilyl)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one;z) 5-(Dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one; aa)6-(Dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one; or bb)8-(Dimethylamino)-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one.
 2. Afunctionalized naphthalene fluorophore having a structure:

where R¹ is a substituent selected from the group consisting of H,C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, an NMR active isotope or an alkyl or alkoxygroup comprising an NMR active isotope, a substituted silyl,trialkylsilyl, diphenylalkylsilyl, triphenylalkylsilyl, a substitutedphosphorous, dialkylphosphino, diphenylphosphino, phenyl, substitutedphenyl, aryl, substituted aryl, heteroaryl, —S(O)R⁴, —S(O)₂R⁴,P(O)(OR⁴)₂, and —C(Y)R⁴ where Y is O, NR⁵, or S; each R² is a halogen,an NMR active isotope or an alkyl or alkoxy group comprising an NMRactive isotope, a substituted silyl, trialkylsilyl, diphenylalkylsilyl,triphenylalkylsilyl, a substituted phosphorous, dialkylphosphino,diphenylphosphino, or —N(R⁶)₂; each R³ is H, C₁-C₂₀ alkyl, an NMR activeisotope or an alkyl or alkoxy group comprising an NMR active isotope, asubstituted silyl, trialkylsilyl, diphenylalkylsilyl,triphenylalkylsilyl, a substituted phosphorous, dialkylphosphino,diphenylphosphino, or combined as ═O; each R⁴, R⁵ and R⁶ isindependently selected from H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, asubstituted silyl, trialkylsilyl, diphenylalkylsilyl,triphenylalkylsilyl, a substituted phosphorous, dialkylphosphino,diphenylphosphino, an NMR active isotope or an alkyl or alkoxy groupcomprising an NMR active isotope, substituted or unsubstituted phenyl,aryl, heteroaryl, benzyl, or two R⁶ groups on an R² group may cometogether to form a cyclic structure; X is CH₂, C(R⁶)₂, C(CO₂Alkyl)₂, O,NTs, NH, NCOR⁵ or NR⁵; n is an integer from 0 to 2; m is an integer from1 to 4, provided that either R¹ is one of —S(O)R⁴, —S(O)₂R⁴, P(O)(OR⁴)₂,and —C(Y)R⁴ or the R³ groups are combined as ═O wherein the NMR isotopeis selected from ²H, ¹³C, ¹⁹F, or ³¹P.
 3. The functionalized naphthalenefluorophore of claim 2, wherein at least one of the R¹, R², R³, R⁴, R⁵or R⁶ groups comprises an NMR active isotope or an alkyl or alkoxy groupcomprising an NMR active isotope, where the NMR active isotope isselected from ²H, ¹³C, ¹⁹F, or ³¹P.
 4. The functionalized naphthalenefluorophore of claim 2, wherein at least one of the R¹, R², R³, R⁴, R⁵or R⁶ groups comprises a substituted silyl, trialkylsilyl,diphenylalkylsilyl, triphenylalkylsilyl, a substituted phosphorous,dialkylphosphino, or diphenylphosphino group.
 5. The functionalizednaphthalene fluorophore of claim 2, wherein at least one of the R¹, R²,R³, R⁴, R⁵ or R⁶ groups comprises a fatty acid residue.
 6. Thefunctionalized naphthalene fluorophore of claim 2, wherein at least oneof the R¹, R², R³, R⁴, R⁵ or R⁶ groups comprises a substituted orunsubstituted phenyl.
 7. The functionalized naphthalene fluorophore ofclaim 2, wherein R¹ is a substituted or unsubstituted phenyl and the R³groups are combined as ═O.